Regulatory T (T reg) cells are known to play an important role in the control of destructive inflammatory responses (1
). Most frequently studied is the naturally occurring population of CD4+
T reg cells that develops in the thymus. These cells are important in the control of a wide range of immune-mediated pathologies, including autoimmunity, colitis, and chronic infection. Nevertheless, T cells with regulatory function can also be generated in the periphery from the naive T cell pool after, for example, the oral administration of antigen or the targeting of peptide ligands to DCs in vivo (2
T cells can also be generated in the presence of TGF-β (5
Although peripheral T cells can begin to express Foxp3 and acquire regulatory function, the relevance of this pathway under normal physiological conditions remains unclear. This is compounded by the fact that induced Foxp3+ T cells look phenotypically similar to the naturally occurring population. Consequently, it is difficult to determine what proportion of peripheral CD25+Foxp3+ T reg cells had their regulatory function imprinted in the periphery.
The ability to induce T reg cell populations from the naive pool may be of particular benefit in the intestine. The extensive immune system here must cope with the challenge of mounting protective immunity to occasional pathogens while remaining tolerant to dietary antigen and the commensal flora. It may therefore be crucial to generate T reg cells specific for these types of antigen, in addition to those T reg cells selected for their high affinity to self-antigen in the thymus.
DCs are thought to play an important role in the generation of T reg cell responses. DCs present in the gut-associated lymphoid tissue (GALT) possess several functional specializations that suggest they may be capable of inducing regulatory-type responses (11
). However, a clear role for these cells in the extrathymic development of Foxp3+
T reg cells remains to be demonstrated.
Here, we demonstrate that a population of CD103+ DCs found in the mesenteric LNs (MLNs) of normal mice can promote the conversion of naive T cells into Foxp3+ T reg cells. This occurred without any further manipulation of the DC population and was dependent on TGF-β and the vitamin A metabolite, retinoic acid (RA). These results highlight one pathway by which T reg cells may be generated in the periphery under normal conditions.