Enlarged colitogenic T cell population paradoxically supports colitis prevention through the B-lymphocyte-dependent peripheral generation of CD4(+)Foxp3(+) Treg cells.

Intestinal inflammation can be induced by the reconstitution of T/B cell-deficient mice with low numbers of CD4(+) T lymphocytes depleted of CD25(+)Foxp3(+) regulatory T cells (Treg). Using RAG-knockout mice as recipients of either splenocytes exclusively depleted of CD25(+) cells or FACS-purified CD4(+)CD25(-)Foxp3(-) T cells, we found that the augmentation of potentially colitogenic naïve T cell numbers in the inoculum was unexpectedly beneficial for the suppression of colon disease and maintenance of immune homeostasis. Protection against T cell-mediated colitis correlated with a significant increment in the frequency of peripherally-induced CD4(+)CD25(+)Foxp3(+) T (pTreg) cells, especially in the mesenteric lymph nodes, an effect that required the presence of B cells and CD4(+)CD25(-)Foxp3(+) cells in physiological proportions. Our findings support a model whereby the interplay between B lymphocytes and a diversified naïve T cell repertoire is critical for the generation of CD4(+)CD25(+)Foxp3(+) pTreg cells and colitis suppression.