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Results for “thymic selection”

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PubMed1994

The expansion of a CD4+ T cell population bearing a distinctive beta chain in MRL lpr/lpr mice suggests a role for the fas protein in peripheral T cell selection.

MRL lpr/lpr mice suffer from a systemic lupus erythematosus-like autoimmune disease. The lpr mutation impairs the normal transcription of the fas message, the product of which mediates apoptosis and presumably the proper selection of T cells. We have found an early expansion of CD4+ T cells bearing a distinctive V beta 8.3-D beta 1.1-J beta 1.1 T cell receptor beta chain in the periphery of MRL lpr/lpr mice, which was not detected in MRL +/+ mice nor in the thymus of MRL lpr/lpr mice. Thus, since thymic selection is normal in MRL lpr/lpr mice, we propose that the lpr mutation results in defective negative selection at the periphery.

Animals↗
PubMed2003

Cutting edge: self-peptides drive the peripheral expansion of CD4+CD25+ regulatory T cells.

CD4(+)CD25(+) regulatory T cell selection is initiated by high-specificity interactions with self-peptides in the thymus, although how these cells respond to cytokine-derived signals and to re-exposure to self-peptide:MHC complexes in the periphery is not well understood. We have used a transgenic mouse system, in which the peptide that induces thymic selection of a clonal population of CD4(+)CD25(+) regulatory T cells is known, to show that CD4(+)CD25(+) T cells proliferate in response to their selecting self-peptide in vivo. Moreover, they do not proliferate in response to lymphopenia in the absence of the selecting self-peptide, reflecting a low level of expression of the high affinity receptor for IL-7 (CD127) relative to conventional CD4(+) T cells. That their selecting self-peptide is both required for and promotes the peripheral expansion of CD4(+)CD25(+) regulatory T cells may direct their accumulation in sites where the self-peptide is expressed.

Adoptive Transfer↗
PubMed2001

The CD8alphabeta co-receptor on double-positive thymocytes binds with differing affinities to the products of distinct class I MHC loci.

The CD8 co-receptor is essential for TCR-dependent immune recognition and T cell development involving peptides bound to MHC class I (MHCI) molecules. The dominant interaction of CD8 alpha alpha and alpha beta co-receptors is with the alpha3 domain of an MHCI molecule. Whether this interaction is different for the products of various MHCI loci is currently unknown. Here we examine the interaction between H-2K(b) and H-2D(b), the two MHCI molecules in the C57BL / 6 mouse, and CD8 using H-2K(b) and H-2D(b) tetramers. The MHCI molecules bind to the CD8alpha beta co-receptor on double-positive thymocytes with different avidities (H-2K(b) > D(b)). The differences are linked to their respective alpha3 domains. Hence, an H-2D(b)K(b) tetramer comprising D(b)alpha1--alpha2 and K(b)alpha3 domains shows more binding than H-2D(b). We also quantitated the monomeric affinities of CD8alpha alpha and CD8alpha beta for H-2K(b) and H-2D(b). The H-2K(b) interaction with CD8alpha alpha and CD8alpha beta is stronger than that of H-2D(b). Given that T cell repertoire selection of DP thymocytes is a function of both TCR-pMHCI and CD8alpha beta-pMHCI avidities, these differences may explain the dominant role of H-2K(b) as compared to H-2D(b) in CD8 T cell development of C57BL / 6 mice. The influence of allelic and non-allelic alpha3 polymorphisms on thymic selection processes are discussed.

Animals↗
PubMed2005

T cell receptor engagement by peptide-MHC ligands induces a conformational change in the CD3 complex of thymocytes.

The T cell receptor (TCR) can recognize a variety of cognate peptide/major histocompatibility complex (pMHC) ligands and translate their affinity into distinct cellular responses. To achieve this, the nonsignaling alphabeta heterodimer communicates ligand recognition to the CD3 signaling subunits by an unknown mechanism. In thymocytes, we found that both positive- and negative-selecting pMHC ligands expose a cryptic epitope in the CD3 complex upon TCR engagement. This conformational change is induced in vivo and requires the expression of cognate MHC. We conclude that TCR engagement with a cognate pMHC ligand induces a conformational change in the CD3 complex of thymocytes and propose that this marks an initial event during thymic selection that signals the recognition of self-antigen.

Animals↗
PubMed2005

Antigen presentation: lysoyme, autoimmune diabetes, and Listeria--what do they have in common?

We discuss three areas of antigen presentation and macrophage biology being investigated in the laboratory. Using hen egg-white lysozyme as a protein antigen, all the segments of the molecules selected by the class II histocompatibility molecule I-A(k) were identified and characterized. The display of each family of peptides was explained biochemically and quantitated. Conformational isomers of a peptide-major histocompatibility complex (MHC) complex were identified. The relationship between the amounts of peptide-MHC displayed by the antigen-presenting cells and two biologic responses, central thymic selection and T-cell responses after immunization in adjuvant, were examined. The class II MHC molecule of the nonobese diabetic I-Ag7 is being examined for its properties of peptide selection. The objective is to identify the diabetogenic peptides, as well as the repertoire of protein antigens from beta-cells that trigger autoantibodies. The I-Ag7 molecule selects peptides that show very distinctive sequence motifs: one or more acidic residues at the carboxy terminus that interact at the P9 pocket of the binding groove. Finally, the investigations in listeriosis examined the early events in immune induction. More important, we found that Listeria causes marked apoptosis of lymphocytes around infective foci resulting from the apoptogenic properties of the pore-forming molecule Listeriolysin O.

Amino Acid Sequence↗
PubMed1994

Disruption of the determinant hierarchy on a self-MHC peptide: concomitant tolerance induction to the dominant determinant and priming to the cryptic self-determinant.

The presentation of self-peptides in a self-restricted manner plays a critical role in the complex positive and negative selective process of T cell recognition of self-determinants. The population of determinants comprises (i) a dominant set which is efficiently presented and induces clonal elimination or inactivation of the corresponding autoreactive T cells, and (ii) a cryptic set which is not processed efficiently enough to reach the threshold of presentation to make an impact on the T cell repertoire during thymic selection. Here we have studied a self-MHC peptide, Ld 61-85, which as shown in earlier work was able to induce vigorous T cell proliferation in syngeneic animals. Despite the fact that this peptide as a whole is 'cryptic', the fine specificity of the class II restricted response was complex, in that there were three distinct and overlapping T cell determinants: the dominant determinant, Ld 65-80, flanked by two cryptic determinants, Ld 61-75 and Ld 73-85, all of which compete for stimulating in vivo autoreactive T cell proliferative responses. The hierarchy of these determinants bears an interesting relationship to tolerance. Ld 61-85 or Ld 61-80 priming induces proliferation only to Ld 65-80; likewise, tolerance induction to Ld 61-80 prevents elicitation of a subsequent response to Ld 61-80 or Ld 65-80 in the local lymph nodes. However, in the Ld 61-80 tolerant mice, in vivo challenge with Ld 61-80 induces a strong T cell proliferative response directed towards cryptic Ld 61-75.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed2005

Immune tolerance to hepatitis C virus acquired during engraftment of bone marrow transplant.

The CD4+ T-cell response appears to be important for clearance of hepatitis C virus (HCV) in the majority of individuals. We have recently described a series of human leucocyte antigen (HLA)-DR11-restricted T-cell epitopes derived from HCV proteins which enables distinct populations of memory CD4+ T cells to be detected and counted in all nonviraemic HCV subjects. We examined the case of an HLA-DR11+ recipient of a haematopoietic stem-cell transplant who was concurrently infected with HCV from an HLA-DR11+ donor sibling. An acute HCV hepatitis developed and was treated with type I interferon. After successful viral clearance, the recipient demonstrated a selective lack of HCV epitope-specific CD4+ T cells and absence of serological responses compared with the treated donor. The recipient had no evidence of any nonspecific immunosuppression. The subsequent effects of concurrent infection during immune reconstitution are not known in adult humans, but data from murine models suggest this can lead to a skewing of the T-cell repertoire because of thymic selection. From the above observations, it is plausible that the introduction of foreign viral antigen into the thymus may lead to subsequent acquired central tolerance.

Adult↗
PubMed1990

Evidence for extrathymic changes in the T cell receptor gamma/delta repertoire.

The germline repertoire of variable genes for the TCR-gamma/delta is limited. This, together with the availability of several V delta-specific and a C delta-specific mAbs, has made it possible to assess differences in the TCR-gamma/delta repertoire in man. TCR-gamma/delta cells expressing particular V gene segments have been previously shown to be localized in different anatomical sites. In this study, analysis of TCR-gamma/delta V gene segment usage performed on subjects from the time of birth through adulthood revealed striking age-related changes in the TCR-gamma/delta repertoire in peripheral blood. V delta 1+ gamma/delta T cells predominated in thymus as well as in peripheral blood at birth and then persisted as a relatively constant proportion of CD3+ PBL. However, V delta 2+ gamma/delta T cells that constitute a small proportion of the CD3+ cells in thymus and in peripheral blood at birth, then expand and account for the major population of gamma/delta T cells in PBL in adults. No parallel postnatal expansion of V delta 2+ cells in the thymus was observed, even when paired thymus-peripheral blood specimens were obtained on subjects between the ages of 3 d and 8 yr. The subset of V delta 2+ lymphocytes that was expanded in peripheral blood expressed high levels of CD45RO suggesting prior activation of these cells, consistent with the possibility that their expansion might have resulted from exposure to foreign antigens or superantigens. In contrast, V delta 1+ T cells in PBL showed no comparable increase in relative numbers and were either negative or expressed only low levels of CD45RO. Consistent with evidence for extrathymic peripheral expansion of selective TCR-gamma/delta subsets, no link between MHC haplotype and differences in the TCR-gamma/delta V gene usage between individuals was apparent, and identical twins displayed TCR-gamma/delta variable gene segment phenotypes that were strikingly different from one another. The elements that determine the TCR-gamma/delta repertoire in individuals are not known. It is possible that both thymic selection and extrathymic factors may influence the peripheral repertoire. Recently, TCR-gamma/delta+ lymphocytes have been shown to expand markedly in peripheral lymphoid tissues and infectious lesions in response to mycobacterial antigens, and a correlation between mycobacterial responses and TCR-gamma/delta V gene usage has been shown in mice. The data presented here demonstrated peripheral age-related changes in the gamma/delta repertoire and point to the importance of extrathymic expansion of specific gamma/delta subsets in generating the human TCR-gamma/delta repertoire.

Adult↗
PubMed1990

Minor lymphocyte stimulating (Mls) gene products in mice influence their genetic resistance or susceptibility to induction of autoimmune encephalomyelitis.

The role of the major histocompatibility complex (MHC) gene products in the genetics of experimental autoimmune encephalomyelitis (EAE) is well established. Here we demonstrate how non-MHC gene products, stimulatory to T cells specific to myelin basic protein (MBP), can affect the MHC control in determining genetic susceptibility or resistance to induction of EAE. I-As-restricted MBP-specific T cells derived from SJL/J mice are shown to cross-react with Mls-2a gene products. The Mls-2a gene product expressed by (SJL/J X BALB/c)F1 mice tolerize T cells recognizing I-As/MBP and favor the development of I-Es/d-restricted MBP-specific T cells mediating EAE in the (SJL/J x BALB/c)F1 mice. These I-Es/d/MBP-specific T cells, cross-reactive with Mls-1a, and the I-As/MBP-specific T cells, cross-reactive with Mls-2a gene products, are both eliminated by self tolerance mechanisms in the H-2-matched (SJL/J X DBA/2)F1 mice, expressing Mls-1a2a gene products, and thereby confer genetic resistance to EAE on the (SJL/J X DBA/2)F1 mice bearing EAE-permissive MHC alleles. These results reflect a developmental selection of a T cell repertoire to the self antigen MBP, imposed by self tolerance to self Mls gene products, which affect the genetic susceptibility to EAE. These studies also demonstrate that self tolerance to Mls gene products can strengthen the tolerance to organ-specific self antigens such as MBP, which may not be expressed or which are absent in the thymus at the time of thymic selection.

Animals↗
PubMed2006

CD1d- and MR1-restricted invariant T cells: of mice and men.

CD1d-restricted natural killer T cells and MR1-restricted mucosal associated invariant T (MAIT) cells constitute two subsets of unconventional T cells that are phylogenetically conserved. Therefore, they are thought to play an essential role within the immune system. MR1-restricted MAIT cell selection is dependent upon B cells, and their accumulation in the gut lamina propria and mesenteric lymph node requires the commensal bacterial flora. These features suggest that MAIT cells could be involved in tolerance or immunity to infections in the gut. As for natural killer T cells, the recent identification of one endogenous ligand, isoglobotrihexosylceramide, and of a family of bacterial agonists is an important advance for understanding their thymic selection and their role during infections.

Animals↗
PubMed2006

IAN family critically regulates survival and development of T lymphocytes.

The IAN (immune-associated nucleotide-binding protein) family is a family of functionally uncharacterized GTP-binding proteins expressed in vertebrate immune cells and in plant cells during antibacterial responses. Here we show that all eight IAN family genes encoded in a single cluster of mouse genome are predominantly expressed in lymphocytes, and that the expression of IAN1, IAN4, and IAN5 is significantly elevated upon thymic selection of T lymphocytes. Gain-of-function experiments show that the premature overexpression of IAN1 kills immature thymocytes, whereas short hairpin RNA-mediated loss-of-function studies show that IAN4 supports positive selection. The knockdown of IAN5 perturbs the optimal generation of CD4/CD8 double-positive thymocytes and reduces the survival of mature T lymphocytes. We also show evidence suggesting that IAN4 and IAN5 are associated with anti-apoptotic proteins Bcl-2 and Bcl-xL, whereas IAN1 is associated with pro-apoptotic Bax. Thus, the IAN family is a novel family of T cell-receptor-responsive proteins that critically regulate thymic development and survival of T lymphocytes and that potentially exert regulatory functions through the association with Bcl-2 family proteins.

Animals↗
PubMed2001

Murine Schnurri-2 is required for positive selection of thymocytes.

A key step in T cell development involves the positive selection of cells that recognize antigen presented by self-major histocompatibility complex. Yet, the signals that are activated by T cell receptor engagement and lead to cell survival remain unclear. We show here that mice lacking the transcription factor Schnurri-2 (Shn-2), a large metal-finger protein, had severely defective positive selection of CD4+ and CD8+ cells. Drosophila Shn acts as a cofactor of Smad homolog and is required for Decapentaplegic signaling. Vertebrates have at least three Shn orthologs (Shn-1, Shn-2 and Shn-3), which are thought to act as nuclear targets in the bone morphogenetic protein-transforming growth factor-beta-activin signaling pathways. These data raised the possibility that the Smad-Shn-2 complex is involved in the thymic selection of T cells.

Activins↗
PubMed1994

CDR3 length in antigen-specific immune receptors.

In both immunoglobulins (Ig) and T cell receptors (TCR), the rearrangement of V, D, and J region sequence elements during lymphocyte maturation creates an enormous degree of diversity in an area referred to as the complementarity determining region 3 (CDR3) loop. Variations in the particular V, D, and J elements used, precise points of recombination, and random nucleotide addition all lead to extensive length and sequence heterogeneity. CDR3 loops are often critical for antigen binding in Igs and appear to provide the principal peptide binding residues in TCRs. To better understand the physical and selective constraints on these sequences, we have compiled information on CDR3 size variation for Ig H, L (kappa and lambda) and TCR alpha, beta, gamma, and delta. Ig H and TCR delta CDR3s are the most variable in size and are significantly longer than L and gamma chains, respectively. In contrast, TCR alpha and beta chain distributions are highly constrained, with nearly identical average CDR3 lengths, and their length distributions are not altered by thymic selection. Perhaps most significantly, these CDR3 length profiles suggest that gamma/delta TCRs are more similar to Igs than to alpha/beta TCRs in their putative ligand binding region, and thus gamma/delta and alpha/beta T cells may have fundamentally different recognition properties.

Amino Acid Sequence↗
PubMed1989

Relative V beta transcript levels in thymus and peripheral lymphoid tissues from various mouse strains. Inverse correlation of I-E and Mls expression with relative abundance of several V beta transcripts in peripheral lymphoid tissues.

We have measured the relative levels of transcripts for 15 of the 22 known V beta gene segments. The level of transcripts for the highest and lowest expressed V beta gene segment differed by greater than 20-fold in the thymus and an even larger difference was observed in the periphery. The levels of expressions were unrelated to the order of the V beta genes on the chromosome. For most of the V beta gene segments, the relative transcript levels were the same in the thymus and periphery, suggesting that thymic selection in general does not act solely upon the V beta gene segment. One V beta gene segment in the BALB and B10 mice strains was an exception to this rule. V beta 5.2 expression in the periphery of BALB and B10 mice inversely correlated with the expression of the MHC class II molecule I-E. Five V beta gene segments had reduced transcript levels in the periphery of Mls-1a mice compared with their thymic levels or to the levels found in Mls-1b mice. The peripheral level of V beta 3 transcripts vary with MHC and Mls-2 haplotypes. The observation that certain V beta transcript levels are reduced in the periphery when compared with the thymus favors the hypothesis that self tolerance at the T cell level results in the elimination of self-reactive T cells, rather than paralysis by a block at some post-transcriptional step. Finally, the wide variability of V beta gene segment expression in the thymus suggests mechanisms exist to import an early bias to the repertoire. Whether this bias results from differential V beta segment rearrangement rates, differential V beta expression rates, or events occurring after TCR-alpha/beta expression on immature/nonmature thymocyte cell surfaces is yet to be determined.

Animals↗
PubMed1991

Role of CD4 molecule in intrathymic T-cell development.

We have investigated the role of CD4 molecules in intrathymic T-cell repertoire selection. The administration of monoclonal antibody (mAb) to CD4 in organ culture of murine foetal thymus (FTOC) completely inhibited the development of CD4+8- cells, and additional treatment with anti-class II MHC (Ia) mAb caused no further effects on this inhibition. On the other hand, when the potentially autoreactive cells in Mls-1a mice were monitored by expression of the Mls-1a-reactive V beta 6 gene product of T-cell receptor alpha beta (TcR alpha beta), the treatment with anti-CD4 resulted in the appearance of V beta 6-bearing cells to some extent, but this effect was considerably reinforced by the combinatory use of anti-Ia mAb with anti-CD4. In a model system where the bacterial superantigen staphylococcal enterotoxin B serves as self-antigen to deplete V beta 8-bearing cells in FTOC, the depletion of V beta 8+ cells was restored partially by anti-CD4 alone but completely by the combination with anti-Ia. These results suggest that CD4 is indispensable for positive selection of all CD4+8- thymocytes, whereas participation of CD4 in negative selection is only partial. It was also observed that the development of TcR alpha beta-bearing cells in the CD4-8- population was inhibited by the treatment with anti-CD4 mAb. In Mls-1a mice, V beta 6-bearing cells were developed in CD4-8+, CD4+8+, and also in CD4-8- populations after anti-CD4 mAb treatment. It is suggested that TcR alpha beta-bearing CD4-8- cells are possibly originated from CD4+ cells and undergo CD4-mediated thymic selection.

Animals↗
PubMed1989

Selective development of CD4+ T cells in transgenic mice expressing a class II MHC-restricted antigen receptor.

T lymphocytes are predisposed to recognition of foreign protein fragments bound to cell-surface molecules encoded by the major histocompatibility complex (MHC). There is now compelling evidence that this specificity is a consequence of a selection process operating on developing T lymphocytes in the thymus. As a result of this positive selection, thymocytes that express antigen receptors with a threshold affinity for self MHC-encoded glycoproteins preferentially emigrate from the thymus and seed peripheral lymphoid organs. The specificity for both foreign antigen and MHC molecules is imparted by the alpha and beta chains of the T-cell antigen receptor (TCR). Two other T-cell surface proteins, CD4 and CD8, which bind non-polymorphic regions of class II and class I MHC molecules respectively, are also involved in these recognition events and play an integral role in thymic selection. In order to elucidate the developmental pathways of class II MHC-restricted T cells in relation to these essential accessory molecules, we have produced TCR-transgenic mice expressing a receptor specific for a fragment of pigeon cytochrome c and the Ek (class II MHC) molecule. The transgenic TCR is expressed on virtually all T cells in mice expressing Ek. The thymuses of these mice contain an abnormally high percentage of mature CD4+CD8- cells. In addition, the peripheral T-cell population is almost exclusively CD4+, demonstrating that the MHC specificity of the TCR determines the phenotype of T cells during selection in the thymus.

Animals↗
PubMed2002

TOX: an HMG box protein implicated in the regulation of thymocyte selection.

In the thymus, pre-T cell receptor (pre-TCR)--mediated signaling and then TCR-mediated signaling initiate changes in gene expression that result in the maturation of CD4 and CD8 lineage T cells from common precursors. Using gene chip technology, we isolated a murine gene, designated Tox, that encodes a member of the HMG (high-mobility group) box family of DNA-binding proteins. TOX expression is up-regulated by both pre-TCR and TCR activation of immature thymocytes but not by TCR activation of mature naïve T cells. Transgenic mice that express TOX show expanded CD8+ and reduced CD4+ single positive thymocyte subpopulations. We present evidence here that this phenotype results from a perturbation in lineage commitment due to reduced sensitivity to TCR-mediated signaling. This molecular marker of thymic selection events may therefore play a role in establishing the activation threshold of developing T cells and patterning changes in gene expression.

Animals↗
PubMed2003

Gene expression analysis of thymocyte selection in vivo.

Self versus non-self discrimination is a key feature of immunorecognition. Through TCR-activated apoptotic mechanisms, autoreactive thymocytes are purged at the CD4(+)CD8(+) double-positive (DP) precursor stage prior to maturation to CD4(+) or CD8(+) single-positive (SP) thymocytes. To investigate this selection process in vivo, gene expression analysis by oligonucleotide array was performed in TCR transgenic mice. In total, 244 differentially expressed DP thymocyte genes induced or repressed by TCR triggering in vivo were identified. Genes involved in the biological processes of apoptosis, DNA recombination, antigen processing and adhesion are coordinately engaged. Moreover, analysis of gene expression in thymocyte subsets revealed that TCR ligand-induced expression profiles vary according to their developmental stage, with 48 genes showing DP preference and nine showing SP thymocyte preference. Finally, our data suggest that both the extrinsic and the intrinsic apoptosis pathways are operating in thymic selection.

Animals↗