The same self-peptide selects conventional and regulatory CD4+ T cells with identical antigen receptors (original) (raw)
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Adaptation of TCR Repertoires to Self-Peptides in Regulatory and Nonregulatory CD4+ T Cells
The Journal of Immunology, 2007
Currently, it is not understood how the specificity of the TCR guides CD4 ؉ T cells into the conventional lineage (Tconv) vs directing them to become regulatory (Treg) cells defined by the Foxp3 transcription factor. To address this question, we made use of the "Limited" (LTD) mouse, which has a restricted TCR repertoire with a fixed TCR chain and a TCR␣ chain minilocus. The TCR repertoires of Tconv and Treg cells were equally broad, were distinct, yet overlapped significantly, representing a less strict partition than previously seen between CD4 and CD8 T cells. As a group, the CDR3␣ motifs showed a significant trend to higher positive charge in Treg than in Tconv cells. The Tconv and Treg repertoires were both reshaped between thymus and periphery. Reducing the array of peptides presented by MHC class II molecules by introducing the H2-DM o/o mutation into the LTD mouse led to parallel shifts in the repertoires of Tconv and Treg cells. In both cases, the CDR3␣ elements were entirely different and strikingly shortened, relative to normal LTD mice. These peculiar sequences conferred reactivity to wild-type MHC class II complexes and were excluded from the normal repertoire, even among Treg cells, indicating that some forms of self-reactivity are incompatible with selection into the Treg lineage. In conclusion, the Treg repertoire is broad, with distinct composition and characteristics, yet significantly overlapping and sharing structural constraints with the repertoire of conventional CD4 ؉ T cells.
Proceedings of the National Academy of Sciences, 2011
CD4 + CD25 + Foxp3 + regulatory T (Treg) cells are generated during thymocyte development and play a crucial role in preventing the immune system from attacking the body's cells and tissues. However, how the formation of these cells is directed by T-cell receptor (TCR) recognition of self-peptide:major histocompatibility complex (MHC) ligands remains poorly understood. We show that an agonist self-peptide with which a TCR is strongly reactive can induce a combination of thymocyte deletion and CD4 + CD25 + Foxp3 + Treg cell formation in vivo. A weakly cross-reactive partial agonist self-peptide could similarly induce thymocyte deletion, but failed to induce Treg cell formation. These studies indicate that CD4 + CD25 + Foxp3 + Treg cell formation can require highly stringent recognition of an agonist self-peptide by developing thymocytes. They also refine the "avidity" model of thymocyte selection by demonstrating that the quality of the signal mediated by agonist self-peptides, rather than the overall intensity of TCR signaling, can be a critical factor in directing autoreactive thymocytes to undergo CD4 + CD25 + Foxp3 + Treg cell formation and/or deletion during their development.
An MHC-linked locus modulates thymic differentiation of CD4+CD25+Foxp3+ regulatory T lymphocytes
International Immunology, 2006
CD4 1 CD25 1 Foxp3 1 regulatory T lymphocytes are crucial for maintenance of immunological tolerance to self and innocuous non-self, are known to modulate immunity to tumors and infectious agents and can induce transplantation tolerance. Surprisingly, only a single genetic polymorphism is known to modulate regulatory T cell (Treg) development in the thymus, leading to a lethal autoimmune disorder. Here, we show that considerably different levels of Tregs are found in the thymi of distinct common laboratory mouse strains. We demonstrate that distinct levels of phenotypically and functionally identical Tregs develop with similar kinetics in the studied mice, that the responsible locus acts in a thymocyte-intrinsic manner and that levels of thymic Foxp3 1 Tregs correlate to those found in the periphery. Using several congenic mouse strains, we mapped one of the at least two genetic loci capable of quantitatively modulating thymic Treg development to a <2.2 Mb region telomeric to the MHC. Our data indicate that polymorphic genes closely linked to the MHC locus substantially modulate differentiation of Tregs. Identification of responsible genes should help in understanding the mechanisms involved in commitment to the Treg lineage as well as selection of these cells in the thymus.
Alteration of T-cell Receptor Repertoires During Thymic T-cell Development
Scandinavian Journal of Immunology, 2006
The majority of thymocytes die in the thymus, whereas small populations of T cells that are able to specifically recognize an antigen are considered to survive. Although the thymic selection is thought to have a profound effect on T-cell receptor (TCR) repertoire, little is known how TCR repertoire is formed during the thymocyte developmental process. We examined TCRa-and b-chain variable regions (TCRAV and TCRBV) repertoire in thymic T-cell subpopulations from mice bearing different major histocompatibility (MHC) haplotypes. In Balb/c mice, but not C57BL/6, remarkable alterations of the TCR repertoire were observed in mature T-cell subpopulations as previously reported. In contrast, there were no significant differences of TCRBV repertoire between DN3 (CD25 + CD44 ) ) and DN4 (CD25 ) CD44 ) ), and between DN4 and DP. These results suggest that (1) TCR repertoire of mature T cells was formed mainly under the influence of endogenous superantigens, while MHC haplotypes played the least role; (2) the 'b-selection' process during immature stages had little impact on TCRBV repertoire formation; and (3) TCR repertoire in immature T-cell subpopulations was extremely similar between different strains of mice. We thus consider that pre-selection TCR repertoire in immature T cells could be determined by some genetic factors conserved among different strains.
Molecular Signature of Recent Thymic Selection Events on Effector and Regulatory CD4+ T Lymphocytes
The Journal of Immunology, 2005
Natural CD4 + CD25 + regulatory T lymphocytes are key protagonists in induction and maintenance of peripheral T cell tolerance. Their thymic origin and biased repertoire continue to raise important questions on the signals that mediate their development. We validated analysis of MHC class II-capture by developing thymocytes from thymic stroma as a tool to study quantitative and qualitative aspects of the cellular interactions involved in thymic T cell development, and used it to analyze regulatory T cell differentiation in wild type mice. Our data indicate that antigen-presenting cells of bone-marrow origin, but surprisingly and importantly not thymic epithelial cells, induce significant negative selection among the very autoreactive regulatory T cell precursors. This fundamental difference between thymic development of regulatory and effector T lymphocytes leads to development of a regulatory T cell repertoire enriched in cells specific for a selected subpopulation of self-antigens, i.e. those specifically expressed by thymic epithelial cells.
2000
Natural CD4 + CD25 + regulatory T lymphocytes are key protagonists in induction and maintenance of peripheral T cell tolerance. Their thymic origin and biased repertoire continue to raise important questions on the signals that mediate their development. We validated analysis of MHC class II-capture by developing thymocytes from thymic stroma as a tool to study quantitative and qualitative aspects of the cellular interactions involved in thymic T cell development, and used it to analyze regulatory T cell differentiation in wild type mice. Our data indicate that antigen-presenting cells of bone-marrow origin, but surprisingly and importantly not thymic epithelial cells, induce significant negative selection among the very autoreactive regulatory T cell precursors. This fundamental difference between thymic development of regulatory and effector T lymphocytes leads to development of a regulatory T cell repertoire enriched in cells specific for a selected subpopulation of self-antigens, i.e. those specifically expressed by thymic epithelial cells.
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 ␣ 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.
MHC-independent αβT cells: Lessons learned about thymic selection and MHC-restriction
Frontiers in Immunology
Understanding the generation of an MHC-restricted T cell repertoire is the cornerstone of modern T cell immunology. The unique ability of αβT cells to only recognize peptide antigens presented by MHC molecules but not conformational antigens is referred to as MHC restriction. How MHC restriction is imposed on a very large T cell receptor (TCR) repertoire is still heavily debated. We recently proposed the selection model, which posits that newly re-arranged TCRs can structurally recognize a wide variety of antigens, ranging from peptides presented by MHC molecules to native proteins like cell surface markers. However, on a molecular level, the sequestration of the essential tyrosine kinase Lck by the coreceptors CD4 and CD8 allows only MHC-restricted TCRs to signal. In the absence of Lck sequestration, MHC-independent TCRs can signal and instruct the generation of mature αβT cells that can recognize native protein ligands. The selection model thus explains how only MHC-restricted TCR...