Functional specialization of gut CD103+ dendritic cells in the regulation of tissue-selective T cell homing

Abstract

Gut-associated lymphoid tissue (GALT) dendritic cells (DCs) display a unique ability to generate CCR9+ α 4 β 7 + gut-tropic CD8+ effector T cells. We demonstrate efficient induction of CCR9 and α 4 β 7 on CD8+ T cells in mesenteric lymph nodes (MLNs) after oral but not intraperitoneal (i.p.) antigen administration indicating differential targeting of DCs via the oral route. In vitro, lamina propria (LP)–derived DCs were more potent than MLN or Peyer's patch DCs in their ability to generate CCR9+ α 4 β 7 + CD8+ T cells. The integrin α chain CD103 (α E) was expressed on almost all LP DCs, a subset of MLN DCs, but on few splenic DCs. CD103+ MLN DCs were reduced in number in CCR7−/− mice and, although CD8+ T cells proliferated in the MLNs of CCR7−/− mice after i.p. but not oral antigen administration, they failed to express CCR9 and had reduced levels of α 4 β 7. Strikingly, although CD103+ and CD103− MLN DCs were equally potent at inducing CD8+ T cell proliferation and IFN-γ production, only CD103+ DCs were capable of generating gut-tropic CD8+ effector T cells in vitro. Collectively, these results demonstrate a unique function for LP-derived CD103+ MLN DCs in the generation of gut-tropic effector T cells.

The transcriptional repressor HIC1 regulates intestinal immune homeostasis

“…25 Our results showing that Hic1 DT mice had reduced numbers of intestinal T cells could be owing to reduced expression of intestinal homing molecules, resulting in impaired intestinal migration. However, we failed to observe any reduction in expression of a4b7 and CCR9 on T H cells in the presence or absence of HIC1 following activation in the presence of RA (Figure 5a).…”

“…22 Previous studies have shown that mice raised on a diet lacking vitamin A (VAD diet) have defects in T H -cell activation and intestinal migration, resulting in an overall impairment in T-cell-driven immune responses in the intestine. [23][24][25] To test whether RA influenced HIC1 expression in intestinal T H cells, we raised Hic1 Citrine mice on a VAD diet. We found that LP T H cells from VAD mice failed to express HIC1 (Figure 4a), suggesting that HIC1 expression in T H cells in the LP is dependent on the presence of RA.…”

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103+ dendritic cells

“…We and others [6][7][8][9] have identified and characterised a specialised population of MLN DC that express the integrin a E chain, CD103. CD103 1 DC represent a sentinel DC population in the small intestine (SI) and can migrate to the MLN to initiate adaptive immune responses [10].…”

“…One possibility is that these activities are mediated by distinct DC populations and indeed many subtypes of DC have been identified in the gut [4]. It has been proposed that resident gutconditioned DC may favour tolerogenic responses, whereas newly recruited inflammatory DC may drive host protective immunity.Alternatively, tissue-resident DC may adopt distinct functions under homeostatic and inflammatory conditions [4,5].We and others [6][7][8][9] have identified and characterised a specialised population of MLN DC that express the integrin a E chain, CD103. CD103 1 DC represent a sentinel DC population in the small intestine (SI) and can migrate to the MLN to initiate adaptive immune responses [10].…”

Induction of organ‐selective CD4+ regulatory T cell homing

“…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].…”