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.Leukocyte chemoattractant and adhesion receptors direct the systemic trafficking and the microenvironmental positioning of the cells of the immune system and control cell-cell interactions that regulate leukocyte activation in inflammation, immunity and immune pathology [1][2][3][4][5] . Tissue-and inflammation-selective interactions of circulating lymphocytes and other leukocytes with specialized vascular endothelium mediate leukocyte recruitment in an active, multistep process involving tethering (mediated primarily by selectins and α 4 integrins) and rolling (in which the enzyme vascular adhesion protein-1 (ref. 6 ), the lectinlike oxidized LDL receptor-1 (ref. 7 ) and the hyaluronate receptor CD44 can also participate 8,9 ); chemoattractant-induced rapid integrin activation (mediated by chemokine and other G protein-coupled receptors); activation-dependent firm arrest on the vessel wall (mediated by integrins, especially β 2 integrins); and diapedesis in response to chemoattractants. Recruitment can be regulated at any or all of these points, and the implications of this for combinatorial diversity, specificity, and mechanistic resiliency in leukocyte trafficking have been discussed in detail 4 .From the perspective of regional physiology and pathology, selective trafficking provides a mechanism for segregating the specialized immune response modalities characteristic of cutaneous versus systemic or intestinal immune responses and for targeting specialized lymphocyte subsets to particular immune microenvironments, such as the B or T cell zones in lymphoid tissues or the epithelial or subcutaneous tissues in the skin. From the perspective of therapeutics, tissue-and microenvironment-specific homing represents an attractive target for the manipulation of localized immune and inflammatory responses.Recently, substantial progress has been made in identifying cells and molecular mediators that are responsible for imprinting specialized trafficking programs.

Dietary gluten triggers concomitant activation of CD4 + and CD8 + αβ T cells and γδ T cells in celiac disease

“…We find that along with the induction of gluten-specific CD4 + cells, the reintroduction of dietary gluten to celiac patients on a gluten-free diet induces the peripheral appearance of large numbers of activated CD8 + and γδ T cells expressing gut-homing markers. These findings are consistent with the supposition that these T cells are activated and imprinted with gut-homing potential in secondary lymphoid organs by dendritic cells presenting gut-derived antigens (32). Like peripheral blood gluten-specific CD4 + T cells, these cells express surface markers consistent with memory or effector cells, indicating that they are programmed as such before gut recruitment.…”

Imprinting of Skin/Inflammation Homing in CD4+ T Cells Is Controlled by DNA Methylation within the Fucosyltransferase 7 Gene

“…T cell recruitment to peripheral organs is controlled by adhesion molecules acting as address codes to the respective organ (1,2). During first Ag encounter in tissue-draining lymph nodes, T cells upregulate the respective homing receptors that promote their re-entry into the priming organ.…”

IL‐6 promotes immune responses in human ulcerative colitis and induces a skin‐homing phenotype in the dendritic cells and Tcells they stimulate

“…6) compared with expression in noninflamed areas. We do not know in which cell type they are expressed, but both molecules are essential in mechanisms of intestinal homeostasis and oral tolerance [12][13][14]18] (Fig. 1A) or whether the proinflammatory phenotype is a consequence of decreased CX3CR1 and/or RALDH2 (among other possible factors).…”