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PubMed1994

Loss of normal thymic repertoire selection and persistence of autoreactive T cells in graft vs host disease.

To assess the influence of graft vs host disease (GVHD) on T cell development and thymic repertoire selection, a murine transplantation model was chosen, in which donor (B10.BR: Mls-1b, Mls-2b) and recipient (CBA/J: Mls-1a, Mls-2a) mice differ in their minor lymphocyte-stimulating Ag. Mature splenic T cells of donor origin were added to the T cell-depleted bone marrow cells to induce moderate GVHD. When analyzed 5 and 10 wk after transplantation, animals with GVHD, but not disease-free controls, demonstrated aberrant thymic maturation with an increase in single positive, TCRhigh+ thymocytes. Phenotypic analysis of TCR V beta expression in mature thymocytes and peripheral T cells revealed a disruption of negative thymic selection of Mls-reactive T cells with the subsequent emergence of V beta 3+ and V beta 6+ T cells in mice with GVHD but not in controls. Using retroviral-mediated gene transfer to tag mature T cells, these V beta 3+ and V beta 6+ T cells could be shown to be derived from donor bone marrow precursors. Thymocytes expressing V beta 3 and V beta 6 were efficiently activated upon cross-linking of their TCRs and peripheral T cells from mice with GVHD proliferated to host-derived splenocytes in a MLR. When transferred to sublethally irradiated CBA/J recipients, only T cells from mice with GVHD expanded dramatically. These data suggest that the lack of proper thymic selection after bone marrow transplantation results in the survival and persistence of self-reactive T cells, which might be responsible for the autoimmune manifestations of chronic GVHD.

Animals↗
PubMed1994

Thymic repertoire selection by superantigens: presentation by human and mouse MHC molecules.

The initial report of T cell receptor (TCR) V beta-specific thymic selection in mice showed association with expression of H-2E molecules and affected V beta 17a T cells which were present in CD4+8+ double positive thymocytes but deleted from the CD4+ and CD8+ single positive populations. Similar deletions were subsequently reported for V beta 8.1+ and V beta 6+ T cells in Mls-1a mouse strains and for V beta 3+ T cells in Mls-2a/3a strains. The 'Mls antigens' are most effectively presented by H-2E molecules but certain alleles of H-2A molecules can also present these endogenous superantigens. Expression of Mls antigens can cause both V beta-specific thymic deletion and stimulation of peripheral T cells from Mls-negative strains. Another category of 'Mls-like' antigens cause only V beta-specific thymic deletion in H-2E+ strains, affecting V beta 5+ and V beta 11+ T cells. The non-MHC ligands responsible for each of these effects are superantigens analogous to the exogenous bacterial superantigens, which also show TCR V beta-specific stimulatory effects when presented by MHC class II positive antigen-presenting cells. The genes encoding endogenous superantigens in mice were shown to co-segregate with mouse mammary tumour virus integrations (Mtv) and to be the Mtv-LTR orf genes. In vitro translation of Mtv-LTR orf genes identified their products as type II integral membrane glycoproteins with the polymorphic C terminus outside the cell. These polymorphisms correlate with specificity for the different TCR V beta chains. Virtually all TCR V beta-specific negative selection in the mouse thymus can be accounted for by the expression of Mtv or MMTV (the infectious counterparts of Mtv proviral integrants) LTR-orf proteins, presented with H-2E or certain H-2A alleles. It is unlikely that TCR V beta-specific positive selection is due to endogenous superantigens since it does not segregate with Mtv genomes. In humans, HLA-DR molecules appear to be homologous with H-2E in mice whereas HLA-DQ are the homologues of H-2A. H-2E negative mice transgenic for HLA-DR alpha chain express a mouse/human heterodimeric molecule which presents Mtv superantigens causing TCR V beta-specific deletion. Such trans-species class II molecules are also effective in TCR V beta-specific positive selection of V beta 2+, V beta 6+ and V beta 10+ T cells. Taken together, these results show that human MHC class II molecules can interact with the murine T cell repertoire.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

[Neurofilament expression in thymic epithelial tumors and anti-axonal autoantibodies in myasthenia gravis: a model for autoimmunity by abnormal T cell selection].

Thymic epithelial tumors from myasthenia gravis (MG) patients and non-neoplastic thymuses were investigated by immunohistochemistry for the expression of neurofilament (NF) epitopes. There was little immunoreactivity confined to the medulla in non-neoplastic thymuses and a faint staining only for a 200 kD NF epitope in medullary and mixed thymomas. In contrast, cortical thymomas and well-differentiated thymic carcinomas expressed epitopes of the 68 kD and 160 kD NF. Demonstrating anti-axonal and anti-NF autoantibodies in thymoma patients we conclude that "false-positive T cell selection" is a mechanism of autoimmunity in paraneoplastic MG.

Autoantibodies↗
PubMed1999

Timing and casting for actors of thymic negative selection.

We have recently proposed a new model for the differentiation pathway of alphabeta TCR thymocytes, with the CD4 and CD8 coreceptors undergoing an unexpectedly complex series of expression changes. Taking into account this new insight, we reinvestigated the timing of thymic negative selection. We found that, although endogenous superantigen-driven thymic negative selection could occur at different steps during double-positive/single-positive cell transition, this event was never observed among CD4lowCD8low TCRint CD69+ thymocytes, i.e., within the first subset to be generated upon TCR-mediated activation of immature double-positive cells. We confirm a role for CD40/CD40L interaction, and the absence of involvement of CD28 costimulation, in thymic deletion in vivo. Surprisingly, we found that thymic negative selection was impaired in the absence of Fas, but not FasL, molecule expression. Finally, we show involvement in opposing directions for p59fyn and SHP-1 molecules in signaling for thymic negative selection.

Animals↗
PubMed2003

Impaired thymic negative selection causes autoimmune graft-versus-host disease.

Animal models with impaired thymic negative selection do not always cause autoimmune diseases despite the development of an autoreactive T-cell repertoire. We investigated the requirements for the development of systemic autoimmune disease by using bone marrow chimeras that lacked expression of major histocompatibility complex (MHC) class II on thymic antigen-presenting cells (APCs), leading to impaired negative selection. We found that impaired negative selection mediated by absence of MHC class II, but not MHC class I, permitted the development of systemic autoimmune disease that is indistinguishable from acute graft-versus-host disease (GVHD). Thymectomy prevented disease, confirming the causal association of the thymus with its development. Adoptive transfer of CD4+ T cells caused GVHD in secondary hosts only when they were irradiated, and cotransfer of peripheral CD4+ and CD8+ T cells from naive mice prevented the disease. These results demonstrate that impaired thymic negative selection can cause lethal autoimmune disease indistinguishable from acute GVHD in the context of a proinflammatory milieu when peripheral regulatory mechanisms are absent.

Adoptive Transfer↗
PubMed1996

The CD43 130-kD peripheral T-cell activation antigen is downregulated in thymic positive selection.

Specific glycoforms of CD43, the major O-glycosylated cell-surface protein on T lymphocytes, can affect cell adhesion according to the types of carbohydrate side chains carried. In the peripheral immune system, CD43 130 kD, which carries core 2 O-glycan structures on its surface, is an activation antigen expressed on both CD4 and CD8 single-positive (SP) T cells. We have previously shown that the 115-kD resting and 130-kD activation glycoforms of murine CD43 are differentially regulated on peripheral SP T cells. In this study, we used transgenic mice expressing T-cell receptors (TCRs) specific for antigens presented by class I and class II major histocompatibility complex (MHC) molecules to determine whether CD43 glycoforms are involved in thymocyte differentiation. Positive selection in these mice results in an increase in the production of CD8 and CD4 SP T cells, respectively, which express the transgenic TCR. Positive selection is also accompanied by the upregulation of TCR, CD69, and CD5. Using these markers to define stages of thymocyte maturation, we found that CD43 130 kD was downregulated in the positive selection of CD4 CD8 double-positive thymocytes expressing a class I but not class II MHC-restricted TCR. These data suggest that core 2 glycosyltransferase (C2GnT) modulated expression of CD43 glycoforms may be involved in thymic selection events.

Animals↗
PubMed2002

Grafts of supplementary thymuses injected with allogeneic pancreatic islets protect nonobese diabetic mice against diabetes.

In nonobese diabetic (NOD) mice, the autoimmune attack of the beta-cells in pancreatic islets is now believed to result from abnormal thymic selection. Accordingly, grafts of thymic epithelium from NOD donors to athymic recipients promote autoimmune islet inflammation in normal strains, and intrathymic islet grafts decrease the incidence of disease in NOD animals. Two competing hypotheses of abnormal thymic selection in diabetic mice have been proposed: deficient negative selection with poor elimination of aggressive organ-specific T cells vs. deficient positive selection of protective T regulatory cells. We have now addressed these alternatives by grafting, into young NOD mice whose own thymus was left intact, newborn NOD thymuses containing allogeneic pancreatic islets. If the NOD defect represented poor negative selection, these animals would develop disease at control rates, as the generation of autoreactive T cells proceeds undisturbed in the autologous thymus. In contrast, if NOD thymuses are defective in the production of T regulatory cells, lower disease incidence is expected in the chimeras, as more protective cells can be produced in the grafted thymus. The results show a reduced incidence of diabetes in the chimeras (24%) as compared with control (72%) NOD mice, throughout adult life. We conclude that amelioration of NOD mice by intrathymic islet grafts is not caused by enhanced negative selection and suggest that autoimmune diabetes in this system is the result of inefficient generation of T regulatory cells in the thymus.

Animals↗
PubMed2001

TNF and Fas-induced apoptosis during negative selection in thymic nurse cells.

Apoptosis of thymocytes associated with thymic nurse cells (TNCs) has been well-documented. TNCs selectively bind and internalize immature alphabeta TCRlo CD4+ CD8+ thymocytes in vitro. A subset of the internalized population matures to the alphabeta TCRhi CD69hi stage of development while the fraction that remains within the cytoplasm dies through the process of apoptosis. Negative selection by thymic cortical epithelial cells has been reported, but little is known about the apoptotic pathway(s) employed to facilitate the death signal. Using the TNC line tsTNC-1 that was reported earlier to maintain the ability to internalize alphabeta TCRlo CD4+ CD8+ cells in vitro, we investigated the role of Fas and TNFalpha in TNC-induced apoptosis. Our initial studies revealed that tsTNC-1 cells express both FasL and TNFalpha apoptosis of triple positive cells was shown to be reduced approximately 50% in co-cultures of tsTNC-1 cells and thymocytes in the presence of either anti-TNFalpha or Fas-Fc. When maximum effective concentrations of both TNFalpha, and Fas-Fc were added to these co-cultures, apoptotic death was further reduced to approximately 68%. These results suggest that both TNFalpha and Fas apoptotic pathways are active during thymocyte selection by TNCs.

Apoptosis↗
PubMed1991

Co-engagement of CD8 with the T cell receptor is required for negative selection.

Although it is established that the CD8 and CD4 co-receptors are involved in T-lymphocyte recognition and activation in the periphery, it is less clear whether these molecules participate in thymic selection events. Analysis of thymic selection in mice transgenic for T cell-receptor genes or for major histocompatibility complex (MHC) genes, or mice injected with antibodies against CD8, CD4 or MHC molecules, is consistent with the participation of CD8 and CD4 in thymic selection. But antibody-mediated crosslinking of surface receptors in thymic organ cultures has indicated that CD8 is not involved in thymic deletion. We show here that mice transgenic for a mutant MHC class I molecule that cannot interact with CD8 do not delete CD8-dependent T cells reactive with the wild-type molecule. This finding unequivocally establishes that for negative selection in the thymus, CD8 must interact with the same MHC class I molecule as the T cell receptor.

Animals↗
PubMed2024

Aire mediates tolerance to insulin through thymic trimming of high-affinity T cell clones.

Insulin is a central autoantigen in the pathogenesis of T1D, and thymic epithelial cell expression of insulin under the control of the Autoimmune Regulator (Aire) is thought to be a key component of maintaining tolerance to insulin. In spite of this general working model, direct detection of this thymic selection on insulin-specific T cells has been somewhat elusive. Here, we used a combination of highly sensitive T cell receptor transgenic models for detecting thymic selection and sorting and sequencing of Insulin-specific CD4+ T cells from Aire-deficient mice as a strategy to further define their selection. This analysis revealed a number of unique t cell receptor (TCR) clones in Aire-deficient hosts with high affinity for insulin/major histocompatibility complex (MHC) ligands. We then modeled the thymic selection of one of these clones in Aire-deficient versus wild-type hosts and found that this model clone could escape thymic negative selection in the absence of thymic Aire. Together, these results suggest that thymic expression of insulin plays a key role in trimming and removing high-affinity insulin-specific T cells from the repertoire to help promote tolerance.

Animals↗
PubMed1999

Self-reactive T cells selected on thymic cortical epithelium are polyclonal and are pathogenic in vivo.

Positive selection of CD4+ T cells requires that the TCR of a developing thymocyte interact with self MHC class II molecules on thymic cortical epithelium. In contrast, clonal deletion is mediated by dendritic cells and medullary epithelium. We previously generated K14 mice expressing MHC class II only on thymic cortical epithelium. K14 CD4+ T cells were positively, but not negatively, selected and had significant in vitro autoreactivity. Here, we examine the function of these autoreactive CD4+ T cells in more detail. Analysis of a series of K14-derived T hybrids demonstrated that the autoreactive population of CD4+ T cells is phenotypically and functionally diverse. Purified K14 CD4+ T cells transferred into lethally irradiated wild-type B6 mice cause acute graft vs host disease with bone marrow failure. Further, these autoreactive CD4+ T cells cause hypergammaglobulinemia and the production of autoantibodies when transferred into unirradiated wild-type hosts. Thus, positive selection by normal thymic cortical epithelial cells, unopposed by negative selection, produces polyclonal CD4+ T cells that are pathologic.

Acute Disease↗
PubMed1996

MHC bias of Mls-1 recognition is not influenced by thymic positive selection.

In contrast to T cell recognition of conventional peptide/MHC, T cell recognition of superantigen is not MHC-restricted. However, an influence of MHC polymorphism on specificity is consistent with accumulating data suggesting a TCR/MHC interaction during T cell recognition of superantigen. We have previously shown that T cells from V beta 8.1 beta-chain transgenic mice show an unexpected bias against recognition of Mls-1 presented by H-2d spleen cells. In the current studies we have examined whether thymic positive selection in H-2d mice, which selects T cells that see conventional antigen preferentially in the context of H-2d, is able to overcome the strong bias against recognition of Mls-1/H-2d. The data show that transgenic T cells from both H-2d and H-2k mice have comparable reactivity. The failure of thymic positive selection to overcome the bias against Mls-1/H-2d suggests that the orientation of the putative TCR/MHC interaction during recognition of Mls-1 is not the same as during recognition of conventional peptide/MHC.

Animals↗
PubMed2001

Downregulated expression of Ly-6-ThB on developing T cells marks CD4+CD8+ subset undergoing selection in the thymus.

Interaction of TCRs on CD4+CD8+ immature T cell with MHC-peptide complexes on stromal cells is required for positive and negative selection in the thymus. Identification and characterization of a subpopulation of CD4+CD8+ thymocytes undergoing selection in the thymus will aid in understanding the mechanisms underlying lineage commitment and thymic selection. Herein, we describe the expression of Ly-6 ThB on developing thymocytes. The majority of CD4+CD8+ thymocytes express Ly-6 ThB at high levels. Its expression is downregulated in a subset of CD4+CD8+ thymocytes as well as in mature CD4+CD8- and CD4-CD8+ T cells. More importantly, interaction of TCR/coreceptor with the self-MHC-peptide contributes to the downregulation of ThB expression on developing thymocytes. These findings indicate that downregulation of ThB on CD4+CD8+ thymocytes identifies a unique subset (CD4+CD8+ThBneg-low) of thymocytes that has received the initial signals for thymic selection but have not yet downregulated the CD4 and CD8 cell surface expression. In addition, these results also indicate that a high frequency (approximately 20-40%) of CD4+CD8+ immature thymocytes receive these initial signals during thymic selection.

Animals↗
PubMed2002

Different role of Apaf-1 in positive selection, negative selection and death by neglect in foetal thymic organ culture.

Apoptotic protease-activating factor 1 (Apaf-1) is a component of the apoptosome which is required for the activation of procaspase-9. As Apaf-1 knockout (KO) (Apaf-1-/-) mice die before birth, the role of Apaf-1 during thymic selection was investigated using 5 day foetal thymic organ culture (FTOC) of thymi obtained at gestational day 15. There was a lower ratio of CD4 single-positive (SP) to CD8 SP cells and decreased apoptosis of CD4+CD8+ (DP) thymocytes from Apaf-1-/- mice compared with wild-type. To determine if these defects resulted in increased production of neglected thymocytes, the Apaf-1-/- mice were crossed with the T-cell receptor (TCR)-alpha-chain KO mice. There was no difference in thymocyte development in the thymi of TCR-alpha-/-Apaf-1-/- and TCR-alpha-/-Apaf-1+/+ mice 5 days after FTOC. To determine if Apaf-1 is involved in apoptosis during death by negative or positive selection, FTOC of the thymus of Apaf-1-/- Db/HY TCR-alphabeta transgenic (Tg) mice was carried out. There was decreased apoptosis of the HY clonal-specific M33+ thymocytes and an increased percentage of the autoreactive CD8+M33+ thymocytes in male, but not female Apaf-1-/- Db/HY TCR Tg mice. Our data suggest that Apaf-1 is not involved in positive selection or death by neglect, but may have a partial role in negative selection during early thymic T-cell development.

Animals↗
PubMed1995

Intermediate steps in thymic positive selection. Generation of CD4-8+ T cells in culture from CD4+8+, CD4int8+, and CD4+8int thymocytes with up-regulated levels of TCR-CD3.

Minor thymus subpopulations representing possible intermediates in thymic positive selection were isolated by cell sorting from bcl-2 transgenic mice, and cultured 1 to 4 days in simple medium to assess their ability to spontaneously develop the surface phenotype of mature T cells. Recovery of cells was in the 60 to 80% range, and no cell proliferation occurred. Only cells originally expressing high, near mature T cell levels of CD3 developed further in culture by down-regulation of CD4 or CD8. The main mature cell product was CD4-8+, regardless of whether the starting phenotype of the CD3high intermediates was CD4+8+, CD4int8+, or CD4+8int; only an intermediate subpopulation expressing the highest levels of CD4 (CD4high8int) produced a dominance of CD4+8- mature progeny. Partial down-regulation of CD8 was therefore not a good indicator of CD4+ T lineage commitment. These and previous results indicate that maturation to the CD8+ T lineage involves a rapid up-regulation of the TCR-CD3 complex, but a relatively slow down-regulation of CD4; it may also involve a partial, transient reduction in surface CD8. In contrast, maturation to the CD4+ T lineage involves a relatively rapid down-regulation of CD8, with maintenance of high levels of CD4. There appears to be a marked asymmetry in the developmental steps leading from CD4+8+ thymocytes to the CD8+ or to the CD4+ T cell lineage.

Animals↗
PubMed1999

MHC structure and autoimmune T cell repertoire development.

Recent work has continued to clarify the relationship between MHC structure and thymic selection that leads to peripheral T cell repertoire development in the pathogenesis of autoimmune diseases. Particular attention has been focused on the nonobese diabetic model of autoimmune diabetes, in which a unique MHC class II molecule (I-Ag7) plays a central role. In the past year, reports on the biochemistry of I-Ag7-combined with analysis of the role of I-Ag7 in T cell repertoire selection--support a model of defective thymic selection as the basis of the association between particular MHC molecules and autoimmune diseases. Analogous work has been done on the structure of the human MHC disease-susceptible and -resistant alleles, DQA1*0301 DQB1*0302 and DQA1*0102 DQB1*0602, and their effect on autoimmune repertoire selection. Comparison of these results (in naturally occurring, spontaneous autoimmune human and murine diabetes), with results in a variety of transgenic and knockout models, has produced an integrated view of how avidity considerations in repertoire selection in the thymus could affect predisposition towards autoimmunity.

Animals↗
PubMed1992

[Presence of thymus-dependent CD4+8+ intestinal intraepithelial lymphocytes and their characteristics in mice].

The purpose of this study was the investigation of the T cell subsets in the gut-associated lymphoid tissues. CD4+8+ T cells were found to appear temporarily in Peyer's patches of mice at 2 to 3 weeks after birth. They disappeared within a short period of time from Peyer's patches, but constantly populated in the intestinal intraepithelial lymphocytes (iIEL). Three to 10% of iIEL were CD4+8+ in the specific pathogen-free (SPF) condition throughout life. They are mature T cells with a high density of CD3 and TcR alpha beta and found to respond to immobilized anti-CD3 antibody. The appearance of CD4+8+ T cells in iIEL was found to be dependent on the thymic selection, since they were absent in the athymic nu/nu mice, and the V beta gene usage was dictated by the pattern of thymic selection. CD4+8+ T cells were not found in the germ-free mice but increased in the SPF old mice. These results indicate that the iIEL contain a unique subset of thymus-derived mature CD4+8+ T cells. These cells may repopulate after the thymic selection in the intestine and increase in response to the intestinal microenvironments.

Aging↗
PubMed2002

Comparison of the frequency of peptide-specific cytotoxic T lymphocytes restricted by self- and allo-MHC following in vitro T cell priming.

T cell recognition of antigenic peptides is thought to occur preferentially in the context of self-MHC. Here, we have tested the ability of four different K(b)-peptide combinations to stimulate self- and allo-restricted CTL responses in three different mouse stains. Responder T cells were primed in vitro with peptide-loaded stimulator cells, followed by limiting dilution assays to measure the number of peptide-specific cytotoxic T lymphocytes (CTL). For three peptides the number of CTL restricted by self-MHC was higher than for allo-MHC-restricted responses, although the difference was surprisingly small (3- to 5-fold). For the fourth peptide there was no detectable difference in the number of self- and allo-restricted CTL. Peptide titration experiments revealed that high avidity CTL were present in both the self- and allo-restricted setting. These data showed that the bias for preferred peptide recognition in the context of self-MHC imposed by positive thymic selection seems marginal. This raised the possibility that the TCR repertoire is inherently biased towards MHC restriction, independent of MHC-guided thymic selection. This was supported by the analysis of mature T cells generated from the thymus of MHC-deficient mice by lectin stimulation. K(b)-restricted CTL were found amongst these T cells at numbers similar to those of allo-restricted CTL. In summary, the data suggest that MHC-restricted peptide recognition is an inherent feature of the TCR repertoire and does not require thymic selection by MHC molecules.

Animals↗