Unexpected Regulatory Role of CCR9 in Regulatory T Cell Development

Abstract

T cells reactive to microbiota regulate the pathogenesis of inflammatory bowel disease (IBD). As T cell trafficking to intestines is regulated through interactions between highly specific chemokine-chemokine receptors, efforts have been made to develop intestine-specific immunosuppression based on blocking these key processes. CCR9, a gut-trophic chemokine receptor expressed by lymphocytes and dendritic cells, has been implicated in the regulation of IBD through mediating recruitment of T cells to inflamed sites. However, the role of CCR9 in inducing and sustaining inflammation in the context of IBD is poorly understood. In this study, we demonstrate that CCR9 deficiency in effector T cells and Tregs does not affect the development of colitis in a microbiota antigen-specific, T cell-mediated model. However, Treg cells express higher levels of CCR9 compared to those in effector T cells. Interestingly, CCR9 inhibits Treg cell development, in that CCR9-/- mice demonstrate a high level of Foxp3+ Tregs, and ligation of CCR9 by its ligand CCL25 inhibits Treg cell differentiation in vitro. Collectively, our data indicate that in addition to acting as a gut-homing molecule, CCR9 signaling shapes immune responses by inhibiting Treg cell development.

Extremely Preterm Infants Have Significant Alterations in Their Conventional T Cell Compartment during the First Weeks of Life

“…T cells trafficking to gut and skin depends on the expression of the homing receptors CCR9/a4b7 and CCR4, respectively, and is implicated in the inflammatory recruitment of Tregs in different immunological settings (42,43). CCR9 signaling also shapes immune responses by inhibiting Treg development (44). We observed that the expression of a4b7, CCR9, and CCR4 was altered within both the total CD4 + T cell and Treg populations (Fig.…”

Food allergen‐sensitized CCR9+ lymphocytes enhance airways allergic inflammation in mice

“…Additionally, a minor increase in CD4 + T regulatory cells was observed in the lungs of successive allergic mice compared to only respiratory allergic mice, which is relevant to the increase in inflammation. It has been shown in vitro that CCR9 can inhibit the development of regulatory T cells through its ligation to CCL25 . This observation suggests that migration of CCR9 + T cells into the lungs could inhibit the proliferation of Tregs, prevent their anti‐inflammatory effect, and, thus, exacerbate pulmonary inflammation.…”

Role of chemokine receptors and intestinal epithelial cells in the mucosal inflammation and tolerance

“…CCR9 2/2 and CCL25 2/2 mice were shown to have increased susceptibility to DSS-induced colitis and take a long time to recover after the withdrawing of DSS [92]. However, Evans-Marin et al [93] showed that deficiency of CCR9 on CD4 + effector and T regs in mice did not affect the development of colitis. These authors further showed that the CCR9-CCL25 interaction inhibits T reg differentiation in culture.…”