Restricted V-segment usage in T-cell receptors from cytotoxic T lymphocytes specific for a major epitope of lymphocytic choriomeningitis virus

Abstract

Cytotoxic T lymphocytes (CTL) play an important role in recovery from a number of viral infections. They are also implicated in virus-induced immunopathology, as best demonstrated in lymphocytic choriomeningitis virus (LCMV) infection of adult immunocompetent mice. In the present study, the structure of the T-cell receptor (TCR) in LCMV-specific CTL in C57BL/6 (B6) mice was investigated. Spleen T cells obtained from LCMV-infected mice were cultured in vitro with virus-infected stimulator cells and then stained with anti-TCR VP antibodies. A skewing of V, usage was noticeable in T cells enriched for their reactivity to LCMV, suggesting that particular V segments are important for the recognition of LCMV T-cell epitopes in B6 mice. To gain more detailed information on the structure of the TCR specific for LCMV epitopes, we studied CTL clones. It has been shown that approximately 90% of LCMV-reactive CTL clones generated in H-2b mice are specific for a short peptide fragment of the LCMV glycoprotein, residues 278 to 286, recognized in the context of the class I major histocompatibility complex molecule, Db. Four CTL clones possessing this specificity were randomly selected from a collection of clones, and their TCR genes were isolated by cDNA cloning or by the anchored polymerase chain reaction. All four clones were found to use V. gene segments belonging to the Va,4 subfamily. By RNA blot analysis, two more clones with the same specificity were also shown to express the Va4 mRNA. In contrast, three different V,, gene segments were used among the four clones examined. J,32.1 was used by three of the clones. Although amino acid sequences in the V(D)J junctional regions were dissimilar, aspartic acid was found in the Va.J and/or V,3D,J3 junctions of all four of these clones, suggesting that this residue is involved in binding the LCMV fragment. Restricted usage of V, and possibly J, segments in the CTL response to a major T-cell epitope of LCMV raises the possibility that immunopathology in LCMV infection can be treated with antibodies directed against such TCR segments. Thus, similar analysis of the TCR in other virus infections is warranted and may lead to therapeutic strategies for immunopathology due to virus infections.

H-2-restricted cytolytic T lymphocytes specific for HLA display T cell receptors of limited diversity.

“…The HLA-Cw3-specific TCR repertoire dearly reflects an enrichment, since among unselected peripheral lymphocytes, <8% of CD8 + cells in DBA/2 mice are VB10 (10, and data not shown). Of the V~10-bearing TCILs (25,26) and JolpHDS58-bearing TCRs (5,19) reported in the literature, none resembles those specific for HLA-Cw3. Moreover, out of 54 additional independent H-2Ka-restricted CTL clones specific for antigens unrelated to HLA-Cw3, only two were found to be V~10, and their junctional regions differ considerably from the HLA-Cw3-reactive V/~10 chains (Casanova et al, manuscript in preparation).…”

Clone-specific T cell receptor antagonists of major histocompatibility complex class I-restricted cytotoxic T cells.

“…Indeed, we have observed such resistance to antagonism in the response of a bulk OVA/K bspecific CTL line (our unpublished observations). On the other hand, T cell responses of less diversity, as have been reported in several cases (30)(31)(32)(33)(34)(35)(36), may be very susceptible to antagonism.…”

Human HLA-A0201-restricted cytotoxic T lymphocyte recognition of influenza A is dominated by T cells bearing the V beta 17 gene segment.

“…Both TCR heterogeneity (8) and conservation (9)(10)(11)(12)(13) to a specific MHC class I peptide complex has been described. Whether immunity after natural infection leads to restrictions on TCR usage remains unclear.…”