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

Abstract

Background & Aims: An unconventional CD4+ TCRα−β+ cell population mediates the development of colitis resembling ulcerative colitis in T-cell receptor α mutant (TCRα−/−) mice. However, the significance of such T cells in individuals with an intact TCRα locus remains unclear. Because a substantial proportion of naturally rearranged TCRα chains fails to pair with TCRβ chains, the aim of this study was to analyze the development of CD4+ TCRα−β+ cells and the course of colitis in the presence of such a TCRα chain. Methods: TCR chain transgenic TCRα−/− mice were generated and compared with wild-type and TCRα−/− 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+ TCRα−β+ cells was assessed by adoptive transfer experiments. Furthermore, the half-life of TCRβ chains was determined by pulse-chase labeling and immunoprecipitation. Results: Transgenic expression of a TCR Vα7.2 chain led to increased frequencies of CD4+ TCRα−β+ cells that caused rapid onset of colitis, reminiscent of, but even more severe than, that in TCRα−/− mice. This unconventional T-cell population displayed a constitutively activated phenotype in normal and transgenic TCRα−/− mice. An extended half-life of newly synthesized TCRβ chains suggests a chaperone function of the TCR Vα7.2 chain in TCRα−/− mice. Conclusions: Physiological TCRα rearrangement can promote the formation of chronically activated CD4+ TCRα−β+ T cells and may play a role in the etiology of UC.