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

Abstract

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.

Concurrent cross‐reactivity of microbiota‐derived epitopes to both self and pathogens may underlie the “Hygiene hypothesis”

“…However, tissues capable of such fine distinction between self and nonself antigens or between “health” and “non‐health” status would not require Tregs for self‐nonself discrimination to begin with. In our opinion, though peripheral conversion of naive T cells into Foxp3 + Tregs has been experimentally observed in vivo, such cells most likely were Foxp3 − Treg precursors already committed and transcriptionally poised at chromatin level to become Foxp3 + Tregs when exiting the thymus to seed the periphery and/or such peripheral conversion of naive CD4 + T cells is directed by thymus‐derived Treg in an antigen‐specific manner …”