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Cross-reactive responses to modified M1??-?? peptides by CD8? T cells that use noncanonical BV genes can describe unknown repertoires.

ABSTRACT: Memory T-cell repertoires are populated by clonotypes selected by an individual's history of antigen exposures. Our previous analysis of middle-age CD8(+) T-cell memory repertoires to the influenza-derived epitope M1(58-66) , described a network of highly cross-reactive BV19 clonotypes responding to M1(58-66) and at least one peptide with a conservative amino acid substitution at either of two TCR contact positions. Here, we report that some substitutions abrogate BV19 responses and favor responses with different BV. Cross-reactive T cells using seven other BV families responded to 12 of 13 peptides tested. BV12 clonotypes define the most extensive cross-reactive network that encompasses seven peptides. We generated 3D networks based on the peptides recognized and BV family used and observed a cluster of five peptides that includes M1(58-66) and another cluster of five peptides that does not include M1(58-66) . The first cluster represents peptides structurally similar to M1(58-66) , and the second represents peptides with more considerable changes in epitope recognition surface. We hypothesize that the second cluster represents the cross-reactive network around another unknown epitope or epitopes. This data supports a model of stable CD8(+) T-cell memory networks that include a substantial contribution from cross-reactive T cells.

SUBMITTER: Petrova GV

PROVIDER: S-EPMC3817827 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Cross-reactive responses to modified M1₅₈-₆₆ peptides by CD8⁺ T cells that use noncanonical BV genes can describe unknown repertoires.

Petrova Galina V GV Gorski Jack J

European journal of immunology 20120920 11

Memory T-cell repertoires are populated by clonotypes selected by an individual's history of antigen exposures. Our previous analysis of middle-age CD8(+) T-cell memory repertoires to the influenza-derived epitope M1(58-66) , described a network of highly cross-reactive BV19 clonotypes responding to M1(58-66) and at least one peptide with a conservative amino acid substitution at either of two TCR contact positions. Here, we report that some substitutions abrogate BV19 responses and favor resp ...[more]

PMID: 22865108

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Project description:The escape of anti-self B cells from tolerance mechanisms like clonal deletion, receptor editing, and anergy results in the production of autoantibodies, which is a hallmark of many autoimmune disorders. In this study, we demonstrate that both germline sequences and somatic mutations contribute to autospecificity of B cell clones. For this issue, we investigated the development of antinuclear autoantibodies (ANAs) and their repertoire in two different mouse models. First, in aging mice that were shown to gain several autoimmune features over time including ANAs. Second, in mice undergoing a chronic graft-versus-host disease (GVHD), thereby developing systemic lupus erythematosus-like symptoms. Detailed repertoire analysis revealed that somatic hypermutations (SHM) were present in all Vh and practically all Vl regions of ANAs generated in these two models. The ANA B cell repertoire in aging mice was restricted, dominated by clonally related Vh1-26/Vk4-74 antibodies. In the collection of GVHD-derived ANAs, the repertoire was less restricted, but the usage of the Vh1-26/Vk4-74 combination was still apparent. Germline conversion showed that the SHM in the 4-74 light chain are deterministic for autoreactivity. Detailed analysis revealed that antinuclear reactivity of these antibodies could be induced by a single amino acid substitution in the CDR1 of the Vk4-74. In both aging B6 and young GVHD mice, conversion of the somatic mutations in the Vh and Vl regions of non Vh1-26/Vk4-74 using antibodies showed that B cells with a germline-encoded V gene could also contribute to the ANA-reactive B cell repertoire. These findings indicate that two distinct pathways generate ANA-producing B cells in both model systems. In one pathway, they are generated by Vh1-26/Vk4-74 expressing B cells in the course of immune responses to an antigen that is neither a nuclear antigen nor any other self-antigen. In the other pathway, ANA-producing B cells are derived from progenitors in the bone marrow that express B cell receptors (BCRs), which bind to nuclear antigens and that escape tolerance induction, possibly as a result of crosslinking of their BCRs by multivalent determinants of nuclear antigens.

Dataset Information

Cross-reactive responses to modified M1??-?? peptides by CD8? T cells that use noncanonical BV genes can describe unknown repertoires.

Publications

Cross-reactive responses to modified M1₅₈-₆₆ peptides by CD8⁺ T cells that use noncanonical BV genes can describe unknown repertoires.

Similar Datasets

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