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Does atrophy of the thymus not effect T-cell selection and tolerance?


The thymus atrophies as age progresses. Does the T cell selection (which happens in the thymus) continue to take place? This doubt came into my mind because in the cadaver we dissected, the thymus was hardly more than scanty fibrous tissue. This definitely should have some effect on immune tolerance right? Is this the reason why the elderly are more prone to autoimmune diseases?

Or is it that selection happens only in children? This line of thought would pose a problem since T-cells are short lived and they continuously need to be produced. Or is it that the site of selection is shifted to some other place?

P.S. I am asking these questions assuming that selection is necessary every time new T cells are made. Correct me if this primary assumption is wrong.


T cells have a long half life (both naive and memory cells have halflives measured in years), especially when taking into account the fact that memory cells in particular can slowly proliferate and renew themselves. An adult human therefore has 20-50 years' worth of accumulated T cells by the time they grow old, and those include both memory cells and naive cells that are potentially able to recognize new antigens. The thymus does continue to produce some new cells at a slow rate, but the backlog of previously produced cells are also able to monitor for pathogens.


Thymic Atrophy: Experimental Studies and Therapeutic Interventions

The thymus is essential for T cell development and maturation. It is extremely sensitive to atrophy, wherein loss in cellularity of the thymus and/or disruption of the thymic architecture occur. This may lead to lower naïve T cell output and limited TCR diversity. Thymic atrophy is often associated with ageing. What is less appreciated is that proper functioning of the thymus is critical for reduction in morbidity and mortality associated with various clinical conditions including infections and transplantation. Therefore, therapeutic interventions which possess thymopoietic potential and lower thymic atrophy are required. These treatments enhance thymic output, which is a vital factor in generating favourable outcomes in clinical conditions. In this review, experimental studies on thymic atrophy in rodents and clinical cases where the thymus atrophies are discussed. In addition, mechanisms leading to thymic atrophy during ageing as well as during various stress conditions are reviewed. Therapies such as zinc supplementation, IL7 administration, leptin treatment, keratinocyte growth factor administration and sex steroid ablation during thymic atrophy involving experiments in animals and various clinical scenarios are reviewed. Interventions that have been used across different scenarios to reduce the extent of thymic atrophy and enhance its output are discussed. This review aims to speculate on the roles of combination therapies, which by acting additively or synergistically may further alleviate thymic atrophy and boost its function, thereby strengthening cellular T cell responses.


Abstract

Foxp3 + Treg cells, which are crucial for maintenance of self-tolerance, mainly develop within the thymus, where they arise from CD25 + Foxp3 – or CD25 – Foxp3 + Treg cell precursors. Although it is known that infections can cause transient thymic involution, the impact of infection-induced thymus atrophy on thymic Treg (tTreg) cell development is unknown. Here, we infected mice with influenza A virus (IAV) and studied thymocyte population dynamics post infection. IAV infection caused a massive, but transient thymic involution, dominated by a loss of CD4 + CD8 + double-positive (DP) thymocytes, which was accompanied by a significant increase in the frequency of CD25 + Foxp3 + tTreg cells. Differential apoptosis susceptibility could be experimentally excluded as a reason for the relative tTreg cell increase, and mathematical modeling suggested that enhanced tTreg cell generation cannot explain the increased frequency of tTreg cells. Yet, an increased death of DP thymocytes and augmented exit of single-positive (SP) thymocytes was suggested to be causative. Interestingly, IAV-induced thymus atrophy resulted in a significantly reduced T-cell receptor (TCR) repertoire diversity of newly produced tTreg cells. Taken together, IAV-induced thymus atrophy is substantially altering the dynamics of major thymocyte populations, finally resulting in a relative increase of tTreg cells with an altered TCR repertoire.


Thymus Atrophy and Double-Positive Escape Are Common Features in Infectious Diseases

The thymus is a primary lymphoid organ in which bone marrow-derived T-cell precursors undergo differentiation, leading to migration of positively selected thymocytes to the T-cell-dependent areas of secondary lymphoid organs. This organ can undergo atrophy, caused by several endogenous and exogenous factors such as ageing, hormone fluctuations, and infectious agents. This paper will focus on emerging data on the thymic atrophy caused by infectious agents. We present data on the dynamics of thymus lymphocytes during acute Trypanosoma cruzi infection, showing that the resulting thymus atrophy comprises the abnormal release of thymic-derived T cells and may have an impact on host immune response.

1. Introduction

The thymus is a primary lymphoid organ in which bone marrow-derived T-cell precursors undergo differentiation, leading to migration of positively selected thymocytes to the T-cell-dependent areas of secondary lymphoid organs [2]. Interactions between thymocytes and specialized thymic microenvironmental cells (thymic epithelial cells, macrophages, dendritic cells, and fibroblasts) support and drive T-cell differentiation from bone marrow-derived precursors, by means of a series of interactions including receptor/coreceptor interactions, cytokines, chemokines, and hormones [3–7], as illustrated in Figure 1.


Intrathymic differentiation of T cells. Lymphocyte differentiation initiates when T-cell precursors enter the thymus through postcapillary venules located at corticomedullary junction. After entering the organ, cells interact with the thymic microenvironment (thymic epithelial cells, macrophages, dendritic cells, and fibroblasts), which ultimately lead to their proliferation and TCR rearrangement. Interactions between thymocytes and specialized thymic microenvironmental cells support and direct T cell differentiation by means of a series of interactions including receptor/coreceptor interactions (MHC-TCR, Integrin/ECM Proteins), cytokines (IL-1, IL-2, IL-3, IL-6, IL-7, IL-8, IFN-gamma), chemokines (as CCL25, CXCL12, CCL21), and hormones, with corresponding receptors. At the subcapsular zone, these thymocytes undergo TCR beta chain rearrangement and selection. Double-positive thymocytes migrate through the cortex and initiate TCR testing (positive selection). Positively selected thymocytes, located at the medulla, are screened for self-reactivity through negative selection. Residence in the medulla is followed by emigration, which is regulated by sphingosine-1-phosphate and its receptor (S1P1). Adapted from [1].

Thymopoiesis starts at the time that a T-cell precursor enters the thymus and interacts with local microenvironmental cells, which ultimately lead to their proliferation and further differentiation to the T-cell lineage. Various types of interactions take place, including those mediated by the class I and class II major histocompatibility complexes (MHC) expressed by microenvironmental cells, extracellular matrix proteins (ECM) such as laminin, fibronectin, and collagen, chemokines (as CCL25, CXCL12, CCL21), lectins such as galectin-3, various typical cytokines (IL-1, IL-2, IL-3, IL-6, IL-7, IL-8, IFN-gamma, and others), sphingosin-1-phosphate (S1P1), and hormones (thymulin, thymopoietin, thymosin-a1) [2, 5, 8–13]. T-cell differentiation depends on T-cell receptor (TCR) gene rearrangement and membrane interaction with MHC molecules.

The mechanisms by which progenitors home to the thymus have been suggested to be similar to those used by leukocytes to enter lymph nodes (selectins, chemokines receptors, and integrins) [1, 14, 15]. As soon as these thymic settling progenitors (TSP) enter the thymus close to the cortico-medullary junction, they generate early T-cell progenitors (ETP) or double-negative DN1 thymocytes, known to be CD117/c-KIT + , CD44 + CD25 − [16]. ETP or DN1 thymocytes evolve to DN2 and DN3 thymocytes that migrate to the subcapsular zone of the thymic lobules, where they rearrange the genes encoding the TCR beta chain, express pre-TCR receptor, and proliferate.

At the DN3 stage, the CXCL12/CXCR4 interaction contributes thymocyte proliferation and differentiation towards the DN4 and subsequently CD4 + CD8 + (DP) stage [1, 17]. Double-negative thymocytes, TCR − CD4 − CD8 − , represent 5% of total thymocytes. Maturation progresses with the definite acquisition of TCR, CD4, and CD8 expression generating DP double cells, which constitute 75–80% of the whole thymocyte population. Thymocytes that do not undergo a productive TCR gene rearrangement die by apoptosis, whereas those expressing productive TCRs interact with peptides presented by molecules of the major histocompatibility complex (MHC), expressed on microenvironmental cells. The result of this interaction determines the fate of thymocytes [2, 9, 18]. The positively selected thymocytes will escape from apoptosis and become mature CD4 + or CD8 + single-positive (SP) T cells (Figure 1). This is a highly rigorous process, and only a small proportion of the double-positive population survives [19]. Positive selection also results in lineage commitment so that the lymphocytes can be committed to either the CD4 or CD8 single-positive phenotype, depending on the class of MHC molecule with which the TCR interacts.

Intrathymic negative selection is essential to establish self-tolerance in the T-cell repertoire, deleting high-avidity TCR signaling thymocytes reacting to self-peptides presented by microenvironmental cells [2, 11, 18, 20].

Interestingly, along with CD4 + T-cell differentiation, two distinct groups of cells, with opposite roles, have been reported: the classical CD4 + T helper cells (cells that are able to trigger and/or enhance an immune response in the periphery) and regulatory CD4 + CD25 + FOXP3 + T cells, which are able to impair a given immune response [9, 21].

The data summarized above clearly demonstrate that the thymus is vital for the homeostatic maintenance of peripheral immune system, maturing both effector and regulatory T cells (Figure 1).

It has been well documented that the thymus undergoes an age-related atrophy [22]. Under normal circumstances, the decline in thymic cellularity in healthy subjects promotes minimal consequence. Nevertheless, over time, reduced efficacy of the immune system with age increases the rise of opportunistic infections, autoimmunity, and cancer [22–24].

In this paper, we present emerging data regarding accelerated thymus atrophy caused by infected agents and possible impact of this thymic atrophy to the host immune response. Moreover, we show that thymic-derived T cells are involved in the dynamics of lymphocyte populations in secondary lymphoid organs during acute Trypanosoma cruzi infection.

2. Parasite Infection Promotes Thymic Atrophy with CD4 + CD8 + Thymocyte Depletion

As mentioned above, the thymus senses several exogenous agents, responding with atrophy, promoted by viruses (HIV, rabies virus), parasites (Trypanosoma cruzi, Plasmodium berghei, Schistosoma mansoni, and Trichinella spiralis), and fungi (Paracoccidioides brasiliensis and Histoplasma capsulatum) [9, 22, 25–40]. The mechanisms involved in the thymic atrophy in infectious disease are not completely elucidated and may vary. Nevertheless, common histological features occur, including decrease of cortical thymocytes and loss of clear-cut distinction in the corticomedullary region [9, 38, 41–47]. At least in some cases, such atrophy may be transient: biphasic reactions of the thymic cortex, characterized by initial atrophy and further restoration, were reported in experimental infections by Histoplasma capsulatum and Toxoplasma gondii [48, 49].

Thymic atrophy in infectious disease may reflect distinct nonmutually excluding events: decreased number of precursor cell entry into the thymus, lower capacity in thymocyte proliferation, increased thymocyte death, and/or increased exit of thymocytes to peripheral lymphoid tissues (Figure 2).


Possible mechanisms involved in thymic atrophy. I. Decreased number of precursor cells migrating into the thymus, II. Lower capacity in thymocyte proliferation during T-cell differentiation, III. Increased thymocyte death, and/or IV. Exit of immature T cells to peripheral tissues.

Although the migratory capacity of T-cell precursors to colonize the thymus in infectious disease remains unknown, data from the literature suggest that parasite-induced thymus atrophy comprises changes in involvement of proliferation, death, and exit of thymocytes.

3. Impaired Thymocyte Proliferation in T. cruzi-Infected Mice

It has been shown that mitogenic responses of thymocytes from T. cruzi acutely infected mice are reduced due to decrease in interleukin (IL)-2 production, which in turn is associated with high levels of IL-10 and interferon-γ [50]. It has also been suggested that changes in thymocyte subset proportions induced by T. spiralis infection are reflected in a reduced capacity of thymocytes to respond to the T-cell mitogen concanavalin A [45]. In contrast, thymocytes from S. mansoni-infected mice apparently exhibit similar concanavalin A-induced proliferative response, as compared to controls [38]. Conjointly, these data suggest that some (but not all) parasites induce decrease in the ability of thymocytes to proliferate, which in turn account for the resulting thymic atrophy.

4. Thymocyte Apoptosis Is a Common Feature in Acute Parasite Infections

In the vast majority of infectious diseases coursing with thymic atrophy, the major biological event associated with thymocyte loss is cell death by apoptosis, as seem, for example, in experimental models of Trypanosoma cruzi and Plasmodium berghei infection [9]. Although CD4 + CD8 + thymocytes are the main target population in infection, other subsets as DN and SP cells also depleted in infected thymus [30, 32, 42, 63, 64].

Glucocorticoid hormones are strong candidates to promote thymic atrophy and thymocyte death in parasitic infections. Serum glucocorticoid levels are upregulated in acute infections and promote DP thymocyte apoptosis through caspase-8 and caspase-9 activation [9, 56, 57, 65, 66] (Box 1). Such rise in serum glucocorticoids has been reported in experimental parasitic diseases such as malaria, American tripanosomiases or Chagas disease, African trypanosomiases or sleeping sickness, toxoplasmosis, leishmaniasis, and schistosomiasis [51, 56, 67–72]. In experimental acute T. cruzi infection, thymic atrophy and thymocyte depletion have been associated with both TNF and glucocorticoid serum levels [44, 65, 73].

Nevertheless, at least in T. cruzi infection, various and different biological mechanisms seem to be involved. T. cruzi-derived transsialidase, as well as host-derived galectin-3, extracellular ATP, and androgens have been pointed out as candidate molecules to enhance thymocyte death [44, 64, 69, 74–77]. Conversely, typical cytotoxic molecules such as Fas and perforin are not involved in thymus atrophy in T. cruzi infection [78].

5. Acute Infection Can Promote Abnormal Escape of Immature Thymocytes to the Periphery

T-lymphocyte migration is controlled by several molecular ligand/receptor interactions, including those involving ECM proteins, chemokines, and lectins [12, 13, 79–82].

In the thymus of mice acutely infected by T. cruzi or P. berghei alterations in expression of ECM proteins, chemokines, and/or galectin-3 have been described [5, 63, 64, 79, 83], which is in keeping with the abnormal appearance of thymus-derived immature DP lymphocytes in peripheral lymphoid organs and blood from infected hosts. These findings suggest that the premature scape of immature cells from the organ also contributes to the establishment of the thymic atrophy [38, 42, 84, 85]. Accordingly, it has been shown that thymocytes from T. cruzi acutely infected mice exhibited increased migratory responses to fibronectin and that abnormally high numbers of DP T cells migrate from the thymus to peripheral lymphoid organs. [42, 64, 83–86] (Box 2). Studies performed in experimental P. berghei infection have also demonstrated increased expression of ECM proteins, CXCL12 chemokine production, and enhanced migratory response of thymocytes from infected mice, when compared to controls [87].

6. Thymic Changes May Impact on the Immune Response of Infected Animals

Acute T. cruzi infection in mice leads to strong activation of innate and adaptive immune responses. Splenomegaly and expansion in subcutaneous lymph nodes (SCLN) were reported, mediated by persistent T- and B-cell polyclonal activation [63, 88–91]. Conversely, atrophy in thymus and mesenteric lymph nodes (MLN) has been observed along with infection [9, 43, 92]. We have previously demonstrated that MLN atrophy in T. cruzi infection mice was associated with massive lymphocyte apoptosis, mediated by TNF, Fas, and caspase-9 [63, 88, 92]. The role of thymus-derived T cells in secondary lymphoid organ dynamics remains unclear. In order to analyze the role of the thymus upon regional immune response in secondary lymphoid organs from acute T. cruzi infected mice, thymectomized male BALB/c mice or sham-operated counterparts were infected with 100 blood-derived trypomastigotes from Tulahuén strain of T. cruzi. In the peak of parasitemia (18–21 d.p.i), mice were killed, and subcutaneous, mesenteric lymph nodes as well as spleen were analyzed. As demonstrated in Figure 3, thymectomy in noninfected mice does not alter lymphocyte counts in the spleen, SCLN, and MLN. However, absence of thymic-derived T cells during acute infection increased the number of splenocytes (Figure 3). In this respect, it has been demonstrated that thymus-derived γδTCR + T cells removed from the spleen exhibit suppressor activity for T lymphocytes [93]. Moreover, as showed in thymectomized T. cruzi chronically infected animals, thymic removal may act by downregulating immunoregulatory mechanisms, leading to an exacerbation of autoimmune reactions believed to be involved in the generation of myocardial damage [94].


(a)
(b)
(a)
(b) Thymectomy modulates splenic cell numbers during acute Trypanosoma cruzi infection. Mice were thymectomized and, six days later, were infected intraperitoneally by the Tulahuén strain of T. cruzi. Animals were killed at 19 days postinfection, and subcutaneous (SCLN), mesenteric (MLN), lymph nodes and spleen cell numbers were evaluated. (a) Representative data demonstrating TCR expression in CD4 and CD8 T cells in SCLN, MLN, and spleen, analyzed by flow cytometry. (b) Data show fold change of 6–8 animals/group where (white rectangle) represents sham-operated control, (black rectangle) sham-operated infected, (light grey rectangle) thymectomized control, and (dark grey rectangle) thymectomized infected mice. Results were representative of three different experiments and were expressed as mean ± standard deviation, ns: not significant, *

Interestingly, no changes were observed in SCLN cell expansion and MLN atrophy between infected sham and thymectomized mice, suggesting that suppressor T cells migrate preferentially to the spleen (Figure 3). All together, these data indicates that thymic-derived T cells can exert immunoregulatory in the spleen during acute T. cruzi infection.

7. Conclusion

Several pathogens, including T. cruzi, cause thymic atrophy. Although the precise mechanisms underlying this phenomenon are not completely elucidated, most likely it is linked to a particular pathogen-host relationship. Recently, we addressed whether the changes of the thymic microenvironment promoted by an infectious pathogen would also lead to an altered intrathymic negative selection of the T-cell repertoire. By using a T. cruzi acute infection model, we have seen that, despite the alterations observed in the cortex and medullary compartments undergoing a severe atrophy during the acute phase, the changes promoted by the infection in the thymic architecture do not affect the negative selection.

Although the intrathymic checkpoints necessary to avoid the maturation of T cells expressing potentially autoreactive “forbidden” T-cell receptors are present in the acute phase of murine Chagas disease, circulating CD4 + CD8 + T cells have been reported in humans as well as in animals such as mice, chicken, swine, and monkeys [9, 62, 85]. The existence of this unconventional and rare lymphocyte population in the periphery was explained as a premature release of DP cells from the thymus into the periphery, where their maturation into functionally competent single-positive cells continues.

Most importantly, there is considerable evidence of an increased frequency of peripheral CD4 + CD8 + T cells not only during acute T. cruzi infection but also in viral infections. For example, in human immunodeficiency virus or Epstein-Barr virus infections, the percentage of DP cells can increase to 20% of all circulating lymphocytes [95–97]. This fluctuation is also present in the secondary lymph nodes as we demonstrated in the experimental model of Chagas disease, in which DP-cell subset increases up to 16 times in subcutaneous lymph nodes [83, 85]. During the course of infection, these peripheral DP cells acquire an activated phenotype similar to what is described for activated and memory single-positive T cells with high IFN-γ production, CD44 + CD69 + expression, and cytotoxic activity [62].

Furthermore, similar to previous studies showing high cytotoxic activity and effector memory phenotype of extrathymic DP cells in cynomolgus monkeys and in a chimpanzee experimental infection with hepatitis C virus [95], our results indicate that the DP cells purified from peripheral lymphoid tissues of chagasic animals show cytotoxic activity as compared to naïve single-positive CD4 + or CD8 + T cells.

Most likely, the presence of peripheral, mature, and activated DP lymphocytes challenges the perception of the T-cell populations involved in adaptive immune responses during the infection. The presence of peripheral activated DP cells with potentially autoreactive TCR may contribute to the immunopathological events possible related to several pathogen infections. In the Chagas disease model, we have demonstrated that increased percentages of peripheral blood subset of DP cells exhibiting an activated HLA-DR + phenotype are associated with severe cardiac forms of human chronic Chagas disease [62]. The role of these HLA-DR + DP T cells in myocardial damage and host pathologies is unknown. However, correlations between the changes in the numbers of DP T-cell subsets and the extent of inflammatory lesions may represent a clinical marker of disease progression in parasitic infections and may help the design of novel therapeutic approaches for controlling infectious diseases.

Abbreviations

T. cruzi:Trypanosoma cruzi
DP T cells:CD4 + CD8 + double-positive T cells
AIRE:Autoimmune regulator gene
TRAs:Tissue-restricted antigens
TCR:T cell receptor
TEC:Thymic epithelial cells.

Acknowledgments

The work presented here has been partially funded with grants from CNPq, Capes, Faperj, and Fiocruz (Brazil).

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Copyright

Copyright © 2012 Juliana de Meis et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


MURINE MODELS OF ACUTE THYMUS INVOLUTION

As study of thymus function in humans is restricted to noninvasive approaches, which offer limited analysis of complex, intrathymic processes, murine models have proven particularly useful in the analysis of stress-induced thymic atrophy as well as during the recovery phase after the stressor is removed. Direct quantification of thymus function in mice can be performed upon necropsy. Total thymus cellularity, phenotypic analysis of developing thymocytes (CD3/CD4/CD8/CD44/CD25), and histological analysis of the thymus can be used to gain intricate knowledge of thymopoiesis. Moreover, we have adapted the molecular sjTREC real-time PCR assay for the mouse TCR sequences, allowing for quantification of murine TRECs (mTREC) in splenocytes, thymocytes, and whole thymus [ 28 ]. Using this assay of thymopoiesis, coupled with peripheral mouse markers of naïve T cells (CD45RB + , CD62L + , CD44 – ), investigators can now comprehensively monitor thymic function in models of stress-induced involution.

Several small animal models exist using various stressors capable of inducing acute thymic involution (Fig. 1). For example, stress from starvation [ 29 ] and physical restraint [ 30 ] increases glucocorticoid (corticosterone) levels, which mediate thymocyte apoptosis. Similarly, injection of synthetic corticosteroids, such as dexamethasone, can also cause acute thymus involution and have been used as a model system [ 31 , 32 ]. Other murine stress-induced thymic atrophy models incorporate sex steroids such as progesterone and estrogen [ 32 , 33 ] and testosterone [ 34 ]. γ-Irradiation can also induce acute thymic atrophy [ 32 ], reminiscent of clinical irradiation treatments. Viral infection models, such as rabies, measles, and hepatitis, also induce thymic atrophy [ 15 ], reminiscent of HIV-1 infection in humans [ 35 ].

As a model for bacterial sepsis, cecal ligation and puncture (CLP) or purified LPS injection can be used. CLP involves perforation of the intestines, a minor surgery performed under anesthesia, which releases infectious bacteria such as Escherichia coli to induce sepsis and subsequent acute thymic atrophy [ 36 ]. A noninfectious and reproducible model routinely used to study acute thymus involution is endotoxin or the LPS-induced acute thymic atrophy model. LPS is the endotoxin produced by gram-negative bacteria, such as E. coli. Purified LPS can be injected i.p. to induce sepsis and subsequent acute thymic atrophy without complications from surgery or active bacterial infection [ 14 , 37 , 38 ].

Mice treated with LPS (100 μg per mouse, i.p.) develop severe acute thymic atrophy that peaks within 3–5 days [ 37 ]. Thymic atrophy in the mouse can be characterized by loss of thymus weight, loss of DP thymocytes, and loss of mTREC/mg thymus. Using these measurements, we have reported that thymus weight, cellularity, and mTREC/mg thymus continues to decrease for up to 7 days after a single LPS challenge, which is then followed by a rebound in thymus function (Fig. 2) [ 37 ]. Using this model, we have defined the role of LIF as a thymosuppressive agent in stress-induced acute thymic atrophy, which will be reviewed below. We have also used this model to begin to understand the protective effects of the metabolic hormone leptin against LPS-induced acute thymic atrophy, which will also be discussed further.

A single injection of LPS-induced acute thymic atrophy with subsequent recovery. BALB/c mice were treated with saline or LPS (100 μg i.p.) on Day 0, and mice were killed on Days 1, 3, 7, 11, 15, 21, and 28 to monitor thymopoiesis (n=3). Mean thymus weight (A), absolute number of CD4/CD8 DP thymocytes (B), and molecules of mTREC per milligram of thymus tissue (C) ± sem were determined at each harvest time. *, P ≤ 0.05, compared with saline-treated controls [ 37 ].


Is T Cell Negative Selection a Learning Algorithm?

Our immune system can destroy most cells in our body, an ability that needs to be tightly controlled. To prevent autoimmunity, the thymic medulla exposes developing T cells to normal "self" peptides and prevents any responders from entering the bloodstream. However, a substantial number of self-reactive T cells nevertheless reaches the periphery, implying that T cells do not encounter all self peptides during this negative selection process. It is unclear if T cells can still discriminate foreign peptides from self peptides they haven't encountered during negative selection. We use an "artificial immune system"-a machine learning model of the T cell repertoire-to investigate how negative selection could alter the recognition of self peptides that are absent from the thymus. Our model reveals a surprising new role for T cell cross-reactivity in this context: moderate T cell cross-reactivity should skew the post-selection repertoire towards peptides that differ systematically from self. Moreover, even some self-like foreign peptides can be distinguished provided that the peptides presented in the thymus are not too similar to each other. Thus, our model predicts that negative selection on a well-chosen subset of self peptides would generate a repertoire that tolerates even "unseen" self peptides better than foreign peptides. This effect would resemble a "generalization" process as it is found in learning systems. We discuss potential experimental approaches to test our theory.

Keywords: T cell repertoires artificial immune system central tolerance learning by example negative selection self-nonself discrimination.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study in the collection, analyses, or interpretation of data in the writing of the manuscript, or in the decision to publish the results.


Clinical significance

A dysfunctional thymus is often associated with autoimmune disorders and an immunocompromised state. There is quite an array of disorders associated with the thymus. These include, but are not limited to, hypoplastic and hyperplastic thymus, neoplasms of the thymus and syndromic anomalies associated with thymic dysfunction.

Thymoma

Thymic neoplasia includes carcinoid masses, lymphomas as well as germ cell tumors. However, they are not all referred to as thymomas. The term thymoma is reserved for thymic masses that are made up of thymic epithelial cells and their associated small thymocytes. This disorder is rarely seen in children, and most often present in patients older than 40 years old. There is no gender or racial redisposition noted to date.

The tumors are usually found in the anterosuperior mediastinum. However, it can also be included as a differential for an anterior neck mass as it has been observed in the neck, adjacent to the thyroid gland.

The majority of patients present with symptoms relating to a mass effect (i.e. compression of neighbouring structures resulting in complications) others are discovered incidentally during routine workup for myasthenia gravis. The association between thymomas and myasthenia gravis, as well as other autoimmune disorders (i.e. Graves’ disease, pernicious anaemia, pure red cell aplasia, dermatomyositis and polymyositis) is based on the concept that the thymomas contain a lot of immature thymocytes and the changes in the architecture interrupts normal education. It is also possible that there is disturbance of the thymus-blood barrier and self-antigen binding thymocytes can still escape into the medulla and eventually , the general circulation.

They can be classified into non-invasive thymoma, invasive thymoma, and thymic carcinoma. Half of the cases of thymomas are non-invasive and are composed of medullary type thymic epithelial cells, or mixed with both medullary and cortical thymic epithelial cells. The medullary type resembles the normal thymic medulla and therefore contains fewer thymocytes. As a result, they are less likely to become infiltrative (i.e. breaching the capsule). The invasive subtypes are locally invasive and are defined as thymomas that penetrate the capsule into surrounding structures. There can be a mixture of thymocytes, with atypical cells suggesting an aggressive tumour. The most aggressive form is fortunately the least common. The thymic carcinomas often metastasize to the lungs and are composed of lymphoepithelioma-like carcinoma. Histologically, they resemble nasopharyngeal carcinomas that is, they have indistinct boundaries and are arranged in sheets of cells.

Thymic hyperplasia

Another cause of an enlarged thymus is thymic hyperplasia. It is characterized by thymic follicular hyperplasia, i.e. the presence of B-lymphocytes in the thymus. Not only is this occasionally a feature of myasthenia gravis, but it can also be seen in chronic inflammatory conditions as well (including, but not limited to systemic lupus erythematosus, scleroderma and rheumatoid arthritis).

Hypoplasticity and DiGeorge syndrome

In addition to the causes of an increase in the size of the thymus, a prominent cause of a hypoplastic thymus can be observed in DiGeorge Syndrome. A microdeletion of sub-band 2, band 1, region 1 of the long arm of chromosome 22 (i.e. Chr 22q11.2) results in a constellation of symptoms including velocardiofacial defects, parathyroid dysfunction and underdevelopment of the thymus. Consequently, the patient experiences a spectrum of immunodeficiencies, as well as possible autoimmune complications.

The immunodeficiency arises because of defective T-lymphocyte maturation. This also results in poor B-cell maturation as T-helper cells also participate in B-cell growth. A series of autoimmune complications have been observed among patients with DiGeorge syndrome that were not seen in patients of similar ages without the chromosomal deletion. These disorders include autoimmune, haemolytic anaemia, idiopathic thrombocytopenic purpura and juvenile rheumatoid arthritis.

These patients often have an associated suppression of the AIRE gene. Consequently, negative selection in the medulla will be inadequate and the resulting T-cells will bind indiscriminately to self-antigens. While the majority of patients with DiGeorge syndrome developed from a spontaneous mutation, a small fraction of patients inherited the disease.

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Conclusion

Age-related thymic involution is a dynamic process that impacts overall T cell development and central T cell tolerance establishment throughout life. Immunosenscence and inflammaging describe two opposing arms of the aged immune system: immune insufficiency, with regard to infection, vaccination, and tumor surveillance, coupled with increased self-reactivity and chronic, systemic inflammation. The contributions of the aged thymus to the manifestations of immunosenscence and inflammaging have recently come to be appreciated. However, continued investigation into their synergy in the aged immune system is needed. Additionally, as we shift our focus towards improving quality of life with age, research into potential avenues for reversing the adverse effects of age-related thymic involution on the aged T cell immune system is of paramount importance. Moreover, there are numerous areas still to explore in this field with far-reaching applications.


Conclusion

T cell immunity is critical for not only coordinating the adaptive response against pathogens but also for mounting a response against malignancies. However, although the importance of the thymus for generation of an effective TCR repertoire is unquestionable, and there is a clear clinical need for boosting thymic function after immune depleting therapies such as the conditioning required for hematopoietic stem cell transplant (HCT) the importance of postnatal thymic function for clinical outcomes in a broader cohort of cancer patients is only beginning to be appreciated. In particular, wider use of new technologies such as single cell sequencing in particular will allow true evaluation of the breadth of the TCR repertoire and how this relates to pathophysiology of disease and therapeutics. Finally, new strategies are under development to enhance posttransplant T cell recovery and several of those are now in clinical trial, such as IL-7, KGF, IL-22, and SSI.


Does atrophy of the thymus not effect T-cell selection and tolerance? - Biology

Título: Chagasic thymicȊtrophyȍoes not�t negative selectionȋut results in theȎxport of€tivated𠳔+CD8+ T⃎lls in severeȏorms of humanȍisease
Autor(es): Morrot,Ȋlexandre
Granado,Ȏugênia Terra
Pérez,Ȋna Rosa
Barbosa, Suse⃚yse Silva
Milićević, Novica M.
Oliveira,ȍésioȊurélio⃺rias⃞
Berbert, Luiz Ricardo
Meis, Juliana⃞
Takiya,Ȍhristina Maeda
Beloscar, Juan
Wang, Xiaoping
Kont, Vivian
Peterson, Pärt
Bottasso, Oscar
Savino, Wilson
Afiliação: Universidade�ralȍo Rio⃞ Janeiro. Instituto⃞ Microbiologia.⃞partamento⃞ Imunologia. Rio⃞ Janeiro, RJ,ȋrasil /ȏundação OswaldoȌruz. Instituto OswaldoȌruz. Laboratório⃞ Pesquisa sobre o Timo. Rio⃞ Janeiro, RJ,ȋrasil.
Fundação OswaldoȌruz. Instituto OswaldoȌruz. Laboratório⃞ Pesquisa sobre o Timo. Rio⃞ Janeiro, RJ,ȋrasil.
National University of Rosario. School of Medical Sciences. Institute of Immunology. Rosario,Ȋrgentina.
Fundação OswaldoȌruz. Instituto OswaldoȌruz. Laboratório⃞ Pesquisa sobre o Timo. Rio⃞ Janeiro, RJ,ȋrasil / Instituto Nacional⃞Ȍâncer.⃞partamento⃞ PesquisaȌlínica. Rio⃞ Janeiro, RJ,ȋrasil.
University of₾ograd.𠾬ulty of Medicine. Institute of HistologyȊndȎmbryology.₾ograd, Servia.
Fundação OswaldoȌruz. Instituto OswaldoȌruz. Laboratório⃞ Pesquisa sobre o Timo. Rio⃞ Janeiro, RJ,ȋrasil.
Fundação OswaldoȌruz. Instituto OswaldoȌruz. Laboratório⃞ Pesquisa sobre o Timo. Rio⃞ Janeiro, RJ,ȋrasil.
Fundação OswaldoȌruz. Instituto OswaldoȌruz. Laboratório⃞ Pesquisa sobre o Timo. Rio⃞ Janeiro, RJ,ȋrasil.
Universidade�ralȍo Rio⃞ Janeiro. Instituto⃞Ȍiênciasȋiomédicas. Instituto Nacional⃞ȌiênciaȎ Tecnologia⃞ȏármacosȎ Medicamentos. Laboratório⃞ȊvaliaçãoȎ Síntese⃞ Substânciasȋioativas. Rio⃞ Janeiro, RJ,ȋrasil / Universidade�ralȍo Rio⃞ Janeiro. Instituto⃞Ȍiênciasȋiomédicas. Laboratório⃞ Patologia⃎lular. Rio⃞ Janeiro, RJ,ȋrasil.
National University of Rosario. School of Medical Sciences. Institute of Immunology. Rosario,Ȋrgentina.
University of Tartu. Institute of GeneralȊnd Molecular Pathology. Molecular Pathology. Tartu,Ȏstonia.
University of Tartu. Institute of GeneralȊnd Molecular Pathology. Molecular Pathology. Tartu,Ȏstonia.
University of Tartu. Institute of GeneralȊnd Molecular Pathology. Molecular Pathology. Tartu,Ȏstonia.
National University of Rosario. School of Medical Sciences. Institute of Immunology. Rosario,Ȋrgentina.
Fundação OswaldoȌruz. Instituto OswaldoȌruz. Laboratório⃞ Pesquisa sobre o Timo. Rio⃞ Janeiro, RJ,ȋrasil.
Resumo em inglês: Extrathymic𠳔+CD8+ȍouble-positive (DP) T⃎llsȊre increased in some pathophysiologicalȌonditions, including infectiousȍiseases. In the murine model ofȌhagasȍisease, it has𠯮n shown that the protozoan parasite TrypanosomaȌruzi is₫le to target the thymusȊnd induceȊlterations of the thymic microenvironmentȊnd the lymphoidȌompartment. In the€ute phase, this results inȊ severeȊtrophy of the organȊnd⃪rly release ofȍP⃎lls into the periphery. To⃚te, the�t of theȌhanges promotedȋy the parasite infection on thymic⃎ntral tolerance has remainedȎlusive. Herein we show that the intrathymic keyȎlements thatȊre necessary to promote the negative selection of thymocytes undergoing maturationȍuring the thymopoiesis remainsȏunctionalȍuring the€uteȌhagasic thymicȊtrophy. IntrathymicȎxpression of theȊutoimmune regulator𠾬tor (Aire)Ȋnd tissue-restrictedȊntigen (TRA) genes is normal. In𠫝ition, theȎxpression of the proapoptoticȋim protein in thymocytes was notȌhanged, revealing that the parasite infection-induced thymusȊtrophy has no�t on these marker genes necessary to promoteȌlonal⃞letion of T⃎lls. InȊȌhickenȎgg ovalbumin (OVA)-specific T-cell receptor (TCR) transgenic system, the₭ministration of OVA peptide into infected mice with thymicȊtrophy promoted OVA-specific thymocyteȊpoptosis,ȏurther indicating normal negative selection processȍuring the infection. Yet,Ȋlthough the intrathymicȌheckpoints necessaryȏor thymic negative selectionȊre present in the€ute phase ofȌhagasȍisease, weȏound that theȍP⃎lls released into the periphery€quireȊn€tivated phenotype similar to what is⃞scribedȏor€tivated�tor or memory single-positive T⃎lls. Most interestingly, weȊlso⃞monstrate that increased percentages of peripheralȋlood subset ofȍP⃎llsȎxhibitingȊn€tivated HLA-DR+ phenotypeȊreȊssociated with severe⃊rdiacȏorms of humanȌhronicȌhagasȍisease. These⃎lls mayȌontribute to the immunopathologicalȎvents seen in theȌhagasȍisease.
Palavras-chave em inglês: Chagasȍisease
Chagasic ThymicȊtrophy
CD4+CD8+ T⃎lls
Severeȏorms
Humanȍisease
Palavras-chave: Doença⃞Ȍhagas
Atrofia TímicaȌhagásica
Células𠳔 +𠳘 + T
Humanos
Data do documento: 2011
Editor: Public Library of Science
Referência: MORROT,ȊlexandreȎtȊl.Ȍhagasic ThymicȊtrophyȍoes Not�t Negative Selectionȋut Results in theȎxport of€tivated𠳔+CD8+ T⃎lls in Severeȏorms of Humanȍisease. PLoS Negl Tropȍis., v.5, n.8,�,–p,Ȋug.�.
DOI: 10.1371/journal.pntd.0001268
ISSN: 1935-2727
Direito autoral: open�ss
Aparece nas coleções:IOC - Artigos de Periódicos

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