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.