Differential requirement for CARMA1 in agonist-selected T-cell development

Caspase recruitment domain-containing membrane-associated guanylate kinase protein-1 (CARMA1) is a critical component of the NF-κB signaling cascade mediated by TCR engagement. In addition to activation of naive T cells, TCR signaling is important for the development of agonist-selected T-cell subsets such as Treg, NKT cells, and CD8-αα T cells. However, little is known about the role of CARMA1 in the development of these lineages. Here we show that CARMA1-deficient mice (CARMA1−/−) have altered populations of specific subsets of agonist-selected T cells. Specifically, CARMA1−/− mice have impaired natural and adaptive Treg development, whereas NKT cell numbers are normal compared with wild-type mice. Interestingly, CD8-αα T cells, which may also be able to develop through an extrathymic selection pathway, are enriched in the gut of CARMA1−/− mice, whereas memory-phenotype CD4+ T cells (CD62Llow/CD44high) are present at reduced numbers in the periphery. These results indicate that CARMA1 is essential for Treg development, but is not necessary for the development of other agonist-selected T-cell subsets. Overall, these data reveal an important but differential role for CARMA1-mediated TCR signaling in T-cell development.