Exacerbated colitis associated with elevated levels of activated CD4+ T cells in TCRα chain transgenic mice

Background & Aims: An unconventional CD4+ TCRalpha(-)beta(+) cell population mediates the development of colitis resembling ulcerative colitis in T-cell receptor alpha mutant (TCRalpha(-/-)) mice. However, the significance of such T cells in individuals with an intact TCRalpha locus remains unclear. Because a substantial proportion of naturally rearranged TCRalpha chains fails to pair with TCRbeta chains, the aim of this study was to analyze the development of CD4+ TCRalpha(-)beta(+) cells and the course of colitis in the presence of such a TCRalpha chain. Methods: TCR chain transgenic TCRalpha(-/-) mice were generated and compared with wild-type and TCRalpha(-/-) mice by flow cytometric analysis of T lymphocytes with respect to their TCR expression and activation status and by histological analysis of colon tissue. The colitogenic potential of the unconventional CD4+ TCRalpha(-)beta(+) cells was assessed by adoptive transfer experiments. Furthermore, the half-life of TCRbeta chains was determined by pulse-chase labeling and immunoprecipitation. Results: Transgenic expression of a TCR Valpha7.2 chain led to increased frequencies of CD4+ TCRalpha(-)beta(+) cells that caused rapid onset of colitis, reminiscent of, but even more severe than, that in TCRalpha(-/-) mice. This unconventional T-cell population displayed a constitutively activated phenotype in normal and transgenic TCRalpha(-/-) mice. An extended half-life of newly synthesized TCRbeta chains suggests a chaperone function of the TCR Valpha7.2 chain in TCRalpha(-/-) mice. Conclusions: Physiological TCRalpha rearrangement can promote the formation of chronically activated CD4+ TCRalpha(-)beta(+) T cells and may play a role in the etiology of UC.