T Cell Receptor Antagonist Peptides Induce Positive Selection

Howard Hughes Medical Institute, Department of Immunology, University of Washington, Seattle 98195.
Cell (Impact Factor: 33.12). 02/1994; 76(1):17-27. DOI: 10.1016/0092-8674(94)90169-4
Source: PubMed

ABSTRACT We have used organ culture of fetal thymic lobes from T cell receptor (TCR) transgenic beta 2M(-/-) mice to study the role of peptides in positive selection. The TCR used was from a CD8+ T cell specific for ovalbumin 257-264 in the context of Kb. Several peptides with the ability to induce positive selection were identified. These peptide-selected thymocytes have the same phenotype as mature CD8+ T cells and can respond to antigen. Those peptides with the ability to induce positive selection were all variants of the antigenic peptide and were identified as TCR antagonist peptides for this receptor. One peptide tested, E1, induced positive selection on the beta 2M(-/-) background but negative selection on the beta 2M(+/-) background. These results show that the process of positive selection is exquisitely peptide specific and sensitive to extremely low ligand density and support the notion that low efficacy ligands mediate positive selection.

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    ABSTRACT: CD4 and CD8 T cell lineages differentiate through respective thymic selection processes. Here, we report cross-differentiation from the CD8 lineage to CD4 T cells, but not vice versa, predominantly in the large-intestine-associated microenvironment. It occurred in the absence or distal presence of cognate antigens. This pathway produced MHC-class-I-restricted CD4(+)Foxp3(+) Treg (CI-Treg) cells. Blocking T cell-intrinsic TGFβ signaling diminished CI-Treg populations in lamina propria, but it did not preclude the CD8-to-CD4 conversion. Microbiota were not required for the cross-differentiation, but the presence of microbiota led to expansion of the converted CD4 T cell population in the large intestine. CI-Treg cells did not promote tolerance to microbiota per se, but they regulated systemic homeostasis of T lymphocytes and protected the large intestine from inflammatory damage. Overall, the clonal conversion from the CD8 lineage to CD4 T cell subsets occurred regardless of "self" or "nonself." This lineage plasticity may promote "selfless" tolerance for immune balance. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.