Janine L. Coombes

Foxp3(+) regulatory T (T reg) cells play a key role in controlling immune pathological re actions. Many develop their regulatory activity in the thymus, but there is also evidence for development of Foxp3(+) T reg cells from naive precursors in the periphery. Recent studies have shown that transforming growth factor (TGF)-beta can promote T reg cell development in culture, but little is known about the cellular and molecular mechanisms that mediate this pathway under more physiological conditions. Here, we show that after antigen activation in the intestine, naive T cells acquire expression of Foxp3. Moreover, we identify a population of CD103(+) mesenteric lymph node dendritic cells (DCs) that induce the development of Foxp3(+) T reg cells. Importantly, promotion of T reg cell responses by CD103(+) DCs is dependent on TGF-beta and the dietary metabolite, retinoic acid (RA). These results newly identify RA as a cofactor in T reg cell generation, providing a mechanism via which functionally specialized gut-associated lymphoid tissue DCs can extend the repertoire of T reg cells focused on the intestine.

A functionally distinct subset of CD103(+) dendritic cells (DCs) has recently been identified in murine mesenteric lymph nodes (MLN) that induces enhanced FoxP3(+) T cell differentiation, retinoic acid receptor signaling, and gut-homing receptor (CCR9 and alpha4beta7) expression in responding T cells. We show that this function is specific to small intestinal lamina propria (SI-LP) and MLN CD103(+) DCs. CD103(+) SI-LP DCs appeared to derive from circulating DC precursors that continually seed the SI-LP. BrdU pulse-chase experiments suggested that most CD103(+) DCs do not derive from a CD103(-) SI-LP DC intermediate. The majority of CD103(+) MLN DCs appear to represent a tissue-derived migratory population that plays a central role in presenting orally derived soluble antigen to CD8(+) and CD4(+) T cells. In contrast, most CD103(-) MLN DCs appear to derive from blood precursors, and these cells could proliferate within the MLN and present systemic soluble antigen. Critically, CD103(+) DCs with similar phenotype and functional properties were present in human MLN, and their selective ability to induce CCR9 was maintained by CD103(+) MLN DCs isolated from SB Crohn's patients. Thus, small intestinal CD103(+) DCs represent a potential novel target for regulating human intestinal inflammatory responses.

The immune system is pivotal in mediating the interactions between host and microbiota that shape the intestinal environment. Intestinal homeostasis arises from a highly dynamic balance between host protective immunity and regulatory mechanisms. This regulation is achieved by a number of cell populations acting through a set of shared regulatory pathways. In this review, we summarize the main lymphocyte subsets controlling immune responsiveness in the gut and their mechanisms of control, which involve maintenance of intestinal barrier function and suppression of chronic inflammation. CD4(+)Foxp3(+) T cells play a nonredundant role in the maintenance of intestinal homeostasis through IL-10- and TGF-beta-dependent mechanisms. Their activity is complemented by other T and B lymphocytes. Because breakdown in immune regulatory networks in the intestine leads to chronic inflammatory diseases of the gut, such as inflammatory bowel disease and celiac disease, regulatory lymphocytes are an attractive target for therapies of intestinal inflammation.

The integrin CD103 is highly expressed at mucosal sites, but its role in mucosal immune regulation remains poorly understood. We have analyzed the functional role of CD103 in intestinal immune regulation using the T cell transfer model of colitis. Our results show no mandatory role for CD103 expression on T cells for either the development or CD4+CD25+ regulatory T (T reg) cell-mediated control of colitis. However, wild-type CD4+CD25+ T cells were unable to prevent colitis in immune-deficient recipients lacking CD103, demonstrating a nonredundant functional role for CD103 on host cells in T reg cell-mediated intestinal immune regulation. Non-T cell expression of CD103 is restricted primarily to CD11c(high)MHC class II(high) dendritic cells (DCs). This DC population is present at a high frequency in the gut-associated lymphoid tissue and appears to mediate a distinct functional role. Thus, CD103+ DCs, but not their CD103- counterparts, promoted expression of the gut-homing receptor CCR9 on T cells. Conversely, CD103- DCs promoted the differentiation of IFN-gamma-producing T cells. Collectively, these data suggest that CD103+ and CD103- DCs represent functionally distinct subsets and that CD103 expression on DCs influences the balance between effector and regulatory T cell activity in the intestine.