Environmental cues, dendritic cells and the programming of tissue-selective lymphocyte trafficking

Abstract

Lymphocytes are imprinted during activation with trafficking programs (combinations of adhesion and chemoattractant receptors) that target their migration to specific tissues and microenvironments. Cytokines contribute, but, for gut and skin, evolution has cleverly adapted external cues from food (vitamin A) and sunlight (ultraviolet-induced vitamin D3) to imprint lymphocyte homing to the small intestines and T cell migration into the epidermis. Dendritic cells are essential: they process the vitamins to their active metabolites (retinoic acid and 1,25(OH)(2)D3) for presentation with antigen to lymphocytes, and they help export environmental cues through lymphatics to draining lymph nodes, to program the trafficking and effector functions of naive T and B cells.

Figure 1

Vitamin A and the imprinting of small intestine trafficking. Model of diet-induced DC-mediated imprinting of T and B cell trafficking to the small intestines. Vitamin A is obtained through the diet as retinol or as plant carotenes, which are locally processed to retinol. Retinol is oxidized to retinal by alcohol dehydrogenases (ADH), and retinal is then oxidized to the active metabolite retinoic acid (RA) by retinal dehydrogenases (RALDH). The small intestines absorb vitamin A and efficiently process retinol to RA; these retinoids are therefore represented at high concentrations in the gut wall. DCs in the lamina propria process antigen internalized by M cells and are educated by the local environment. For example, transforming growth factor (TGF)-β activated by the epithelium is hypothesized to upregulate CD103 on a subset of DCs. Mucosal DCs, in particular the educated CD103⁺ subset, also express enzymes (ADH, RALDH) necessary for processing retinol to RA. Mucosal DCs bearing processed antigen transport it to the draining MLN, where they present it to naive T cells. Retinol bound to protein can be transported through the lymphatics, and DCs, perhaps especially the CD103⁺ subset, may also transport RA itself as an active cargo. CD103⁺ DCs from the small intestines induce rapid and robust RA-dependent signaling in antigen-reactive naive T cells in the MLN, efficiently imprinting the T cells with small intestine–homing properties by upregulating CCR9 and α₄β₇. RA also inhibits induction of the skin homing receptor CLA. Mechanisms responsible for suppression of CCR4 expression on most gut T cells are not understood. Mucosal DCs also support B cell differentiation into small intestine-homing IgA⁺ ASCs, a process that involves synergy between IL-5 or IL-6, RA and DCs. DCs may present antigen in the context of RA to memory or effector T cells in the lamina propria, as well, potentially reinforcing their expression of small intestine–homing receptors CCR9 and α₄β₇. MAdCAM, mucosal vascular addressin cell adhesion molecule; RAR, retinoic acid receptor; RXR, retinoid X receptor.

Figure 2

Sunshine, vitamin D3 and T cell epidermotropism. (a) Model of sunlight-induced T cell epidermotropism in the context of cutaneous antigenic stimulation and DC imprinting of skin T cell trafficking. Sunlight generates vitamin D3 locally in the skin. UVB rays, which penetrate only the outer layers of skin, generate previtamin D3 from 7-dehydrocholesterol, a precursor that is expressed at uniquely high concentrations in the basal epidermis. Over hours to days, the previtamin undergoes spontaneous isomerization to vitamin D3. DCs express the vitamin D3 hydroxylases CYP27A1 and CYP27B1 and, along with keratinocytes, can metabolize the UVB-induced vitamin to its active form, 1,25(OH)₂D3. In the sun-exposed skin, antigen-presenting DCs therefore generate and present high concentrations of 1,25(OH)₂D3 to memory or effector T cells, which respond by upregulating CCR10 and migrating to the keratinocyte-expressed epidermal chemokine CCL27. Cutaneous DCs also migrate through the lymphatics to present antigens to naive T cells in lymph nodes. Many antigen-reactive naive T cells are imprinted with a skin homing phenotype (CLA⁺CCR4^hiα₄β₇–) that directs their trafficking through the blood into the dermis. DC cytokines such as IL-12, which enhances the expression of CLA, are important, but the factors responsible for CCR4 upregulation and, potentially, CCR8 (not shown) expression, and for suppression of α₄β₇ expression, are not understood. After sun exposure, vitamin D3, or locally generated 25(OH)D3 or 1,25(OH)₂D3, may also be transported by DCs or transported bound to transport proteins to the draining lymph node. Vitamin D3 or its metabolites could be presented along with IL-12 and antigen to naive T cells, thus generating an epidermotropic CCR10⁺, skin-homing T cell population in the primary cutaneous immune response. CLA, cutaneous lymphocyte-associated antigen; RXR, retinoid X receptor; VCAM, vascular cell adhesion molecule; VDR, vitamin D receptor. (b) Concentrations of vitamin D and its metabolites found in human skin and blood. The sun provides a skin-specific signal for imprinting of T cell epidermotropism through the local generation of uniquely high levels of vitamin D3. The effective concentrations of vitamin D3 and its metabolites 25(OH) D3 and 1,25(OH)₂D3 needed for inducing CCR10 expression on T cells are shown. The concentrations of vitamin D3 found in the skin are sufficient for DCs to induce CCR10 expression on responding T cells. However, the concentrations of vitamin D and its metabolites in the blood (circulation) and reported D vitamin concentrations in intestines and other tissues are too low for the efficient induction of CCR10 (discussed in ref. 25).