Limited CD4 T-cell diversity associated with colitis in T-cell receptor α mutant mice requires a T helper 2 environment

Abstract

Background and Aims: T-cell receptor α mutant (TCRα(-/-)) mice spontaneously develop chronic colitis mediated by CD4+ TCRα-β+ T cells. The aim of this study was to analyze the mechanisms of expansion of these cells by characterization of the TCRβ repertoire. Methods: TCRβ repertoire was analyzed by reverse-transcription polymerase chain reaction/Southern blot and DNA sequencing. Clonality of T cells was examined in the lymphoid tissues and colons of TCRα(-/-) mice and interleukin 4-deficient TCRα(-/-) mice. In addition, an in vitro culture system using syngeneic colonic epithelial cells as antigens was used. Results: The clonal expansion of a restricted subset of Vβ8.2+ T cells was characterized by conservation of a single negatively charged amino acid residue in the second position of the complementarity-determining region 3 (CDR3). These T cells were observed in the diseased colon and appendix (cecal patch) of TCRα(-/-) mice, but not germfree TCRα(-/-) mice. Culture of polyclonal T cells from young TCRα(-/-) mice with colonic epithelial cells under T helper 2 conditions resulted in the survival of Vβ8.2+ T cells characterized by the same CDR3 pattern. In addition, the transfer of the cultivated T cells induced mild colitis in recombination-activating gene 1 mutant mice. Conclusions: In the TCRα(-/-) mice, the development of colitis is associated with the presence of a restricted diversity of Vβ8.2+ T-cell subsets characterized by a specific TCR motif. The limited diversity of lamina propria T cells that are derived from naive T cells expanded by reacting with luminal bacterial antigens is likely caused by the survival of these T cells after stimulation with self-antigens in the presence of a T helper 2 environment.