Cutting Edge: CD4-Independent Development of Functional FoxP3+ Regulatory T Cells

The CD4 coreceptor is mandatory for the differentiation and function of conventional MHC class II-restricted T cells, but little is known about its contribution in regulatory T cells (Tregs). We thus investigated the Treg compartment in mice lacking CD4. CD3(+)CD8(-)FoxP3(+) cells were readily detected in the periphery of CD4(-/-) mice, where their percentages were even increased as compared with wild-type animals. These cells had a classical CD25(+)CD152(+)GITR(+) Treg phenotype, were enriched in memory-type Tregs, and displayed a diversified TCR repertoire. Functionally, CD4(-/-) Tregs were equally as suppressive as CD4(+/+) Tregs in vitro as well as in vivo. Hence, the CD4 coreceptor is dispensable for the generation and function of FoxP3(+) Tregs. Furthermore, CD3(+)CD8(-)FoxP3(+) Tregs were also found to develop in the absence of both CD4 and MHC-II molecules, demonstrating that the generation of Tregs can occur independently of MHC-II recognition. The Journal of Immunology, 2009, 183: 4182-4186.