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

Background & Aims: T-cell receptor alpha mutant (TCR alpha(-/-)) mice spont aneously develop chronic colitis mediated by CD4(+) TCR alpha(-)beta(+) T c ells, The aim of this study was to analyze the mechanisms of expansion of t hese cells by characterization of the TCR beta repertoire. Methods: TCR bet a repertoire was analyzed by reverse-transcription polymerase chain reactio n/Southern blot and DNA sequencing. Clonality of T cells was examined in th e lymphoid tissues and colons of TCR alpha(-/-) mice and interleukin 4-defi cient TCR alpha(-/-) mice, In addition, an in vitro culture system using sy ngeneic colonic epithelial cells as antigens was used. Results: The clonal expansion of a restricted subset of V beta 8.2(+) T cells was characterized by conservation of a single negatively charged amino acid residue in the s econd position of the complementarity-determining region 3 (CDR3), These T cells were observed in the diseased colon and appendix (cecal patch) of TCR alpha(-/-) mice, but not germfree TCR alpha(-/-) mice. Culture of polyclon al T cells from young TCR alpha(-/-) mice with colonic epithelial cells und er T helper 2 conditions resulted in the survival of V beta 8.2(+) T cells characterized by the same CDR3 pattern. In addition, the transfer of the cu ltivated T cells induced mild colitis in recombination-activating gene 1 mu tant mice. Conclusions: In the TCR alpha(-/-) mice, the development of coli tis is associated with the presence of a restricted diversity of V beta 8.2 (+) T-cell subsets characterized by a specific TCR motif, The limited diver sity of lamina propria T cells that are derived from naive T cells expanded by reacting with luminal bacterial antigens is likely caused by the surviv al of these T cells after stimulation with self-antigens in the presence of a T helper 2 environment.