Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells

Abstract

Whereas naive T cells migrate only to secondary lymphoid organs, activation by antigen confers to T cells the ability to home to non-lymphoid sites. Activated effector/memory T cells migrate preferentially to tissues that are connected to the secondary lymphoid organs where antigen was first encountered. Thus, oral antigens induce effector/memory cells that express essential receptors for intestinal homing, namely the integrin alpha4beta7 and CCR9, the receptor for the gut-associated chemokine TECK/CCL25 (refs 6, 8, 9). Here we show that this imprinting of gut tropism is mediated by dendritic cells from Peyer's patches. Stimulation of CD8-expressing T cells by dendritic cells from Peyer's patches, peripheral lymph nodes and spleen induced equivalent activation markers and effector activity in T cells, but only Peyer's patch dendritic cells induced high levels of alpha4beta7, responsiveness to TECK and the ability to home to the small intestine. These findings establish that Peyer's patch dendritic cells imprint gut-homing specificity on T cells, and thus license effector/memory cells to access anatomical sites most likely to contain their cognate antigen.

Induction of organ‐selective CD4+ regulatory T cell homing

“…Our data suggest that these populations are not randomly produced, but are rather selectively instructed during antigen-stimulated differentiation, leading to the conversion of naïve-like Treg into effector/memory Treg with distinct homing properties. Thus, naïve-like Treg harbor a high degree of plasticity for the induction of organ-selective HR and respond to local factors of the tissue microenvironment, comparable to that previously reported for conventional T cells [4, [15][16][17][18][19][20][21]. Such a variable configuration with organ-selective HR would allow efficient homing of Treg to various organs, correlating to the site of initial priming.…”

“…Whereas in vitro T cell activation by intestinal DC from PP and mLN is necessary and sufficient to generate a a 4 b 7 + gut-homing phenotype, DC isolated from pLN induce higher levels of selectin ligands than intestinal DC [17][18][19][20]49]. In the current study we also used ex vivo isolated CD11c + DC to stimulate naïve-like Treg in vitro.…”

“…Effector T cells generated in different lymphoid organs display distinct tissue tropism, which is regulated by an organ-specific induction of adhesion molecules and chemokine receptors during T cell priming [4,[15][16][17][18][19][20][21]. For example, T cells activated in mLN and PP draining the gut acquire high levels of the integrin a 4 b 7 , whereas activation in skin-draining peripheral LN (pLN) results in the upregulation of selectin ligands such as P-lig.…”

“…For example, T cells activated in mLN and PP draining the gut acquire high levels of the integrin a 4 b 7 , whereas activation in skin-draining peripheral LN (pLN) results in the upregulation of selectin ligands such as P-lig. Tissuespecific DC have been shown in a number of in vitro and in vivo studies to be involved in the instruction of naïve T cells [4,[17][18][19][20][22][23][24] reported that GALT DC were capable of converting metabolites of dietary vitamin A into retinoic acid (RA), which in turn induced T cell expression of a 4 b 7 and CCR9, leading to the generation of gut-tropic T cells. However, the factors, which are involved in the generation of skin-specific T cell homing in vivo, are largely unknown, although important roles for cytokines including IL-12 and TGF-b have been suggested from in vitro studies [26][27][28].…”

Mucosal delivery of vaccines in domestic animals

“…Chemokine receptors (CCR) and mucosal homing molecules, such as the α 4 β 7 -integrin, are found on effector lymphocytes, and in fact the expression of these receptors is controlled by the imprinting by mucosal DC. For example, in mice only DC derived from Peyer's patches and mesenteric lymph nodes were able to induce expression of α 4 β 7 + and CCR9 + on CD8 + T cells leading to site specific homing of these effector cells to the small intestinal lamina propria [74,109]. CCR9, the receptor for the thymus-expressed chemokine (TECK, CCL 25), is expressed on effector B and T cells and mediates the selective migration of these effector cells to the small intestine in humans and mice [19,87,120].…”