Selective Generation of Gut Tropic T Cells in Gut-associated Lymphoid Tissue (GALT)

Abstract

In the current study, we address the underlying mechanism for the selective generation of gut-homing T cells in the gut-associated lymphoid tissues (GALT). We demonstrate that DCs in the GALT are unique in their capacity to establish T cell gut tropism but in vivo only confer this property to T cells in the presence of DC maturational stimuli, including toll-like receptor-dependent and -independent adjuvants. Thus, DCs from mesenteric LNs (MLNs), but not from spleen, supported expression of the chemokine receptor CCR9 and integrin α4β7 by activated CD8+ T cells. While DCs were also required for an efficient down-regulation of CD62L, this function was not restricted to MLN DCs. In an adoptive CD8+ T cell transfer model, antigen-specific T cells entering the small intestinal epithelium were homogeneously CCR9+α4β7 +CD62Llow, and this phenotype was only generated in GALT and in the presence of adjuvant. Consistent with the CCR9+ phenotype of the gut-homing T cells, CCR9 was found to play a critical role in the localization of T cells to the small intestinal epithelium. Together, these results demonstrate that GALT DCs and T cell expression of CCR9 play critical and integrated roles during T cell homing to the gut.

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.…”

“…Both for conventional T cells [15,19] and for Treg as studied here, in vivo priming of adoptively transferred T cells led to selective induction of a 4 b 7 expression only within mLN, but not within pLN, and, conversely, higher frequencies of E-and P-lig + cells were found within pLN.…”

“…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].…”