Embryonic trafficking of γδ T cells to skin is dependent on E/P selectin ligands and CCR4

Abstract

Dendritic epidermal T cells (DETC) express an invariant Vγ3/Vδ1 T-cell receptor, appear in fetal epidermis, and form a population of resident epidermal T cells. Their temporal development in the thymus has been studied extensively. However, little is known about the mechanisms involved in the embryonic trafficking of DETC from thymus to epidermis. We demonstrate that DETC in adult skin, as well as the DETC precursors in fetal thymus, express E and P selectin ligands (E-and P-lig). Mice deficient in α1,3 fucosyltransferases IV and VII (FTIV/VII) cannot synthesize the carbohydrate motifs that form key elements of these selectin ligands. The numbers of DETC in the epidermis of FTIV/VII −/− mice were dramatically reduced compared with normal mice. However, the development of DETC precursors in fetal thymus was identical in normal and FTIV/VII −/− mice, suggesting that the DETC precursors produced in FTIV/VII −/− mice could not traffic effectively to skin because they lack E-and P-lig. We tested this hypothesis by daily injection of blocking antibodies against E and P selectin into pregnant mice. Mice born from dams treated with anti-selectin antibodies, but not those born from dams treated with isotype control, had significantly diminished numbers of DETC. To test the role of chemokine receptors in DETC skin homing, we examined skin from CCR4 −/− and CCR10 −/− mice, respectively. DETC were significantly reduced in CCR4 −/− mice but were present at normal levels in CCR10 −/− mice. Our results present evidence for the crucial role of trafficking molecules in embryonic migration of DETC precursors to skin. central to host defense against pathogens, and bear T-cell receptors (TCR) that are heterodimers of either α and β or γ and δ TCR genes. T cells with γδ TCR are much less abundant than αβ TCR cells in the adult thymus, blood, and peripheral lymphoid organs but are more abundant in epithelial layers of tissues, such as skin, intestine, lung, and genitourinary tract (1-4). Murine dendritic epidermal T cells (DETC) are a unique population of γδ T cells that reside in murine epidermis. They have a dendritic morphology in situ and express a distinctive invariant Vγ3/Vδ1 TCR that recognizes a putative self-antigen expressed on the damaged, stressed, or transformed keratinocytes (5). In the past decade, significant advances have been made in understanding the roles of DETC in tissue homeostasis and wound healing (6-8). Recently, DETC were shown to contribute to the regression of cutaneous tumors through NKG2D ligation and to regulate autoimmune skin disease (9, 10). DETC also may be important mediators in bridging innate and adaptive immunity of skin through communication with keratinocytes and Langerhans cells (11).The thymus is a unique site that provides an inductive environment for T-lineage commitment and V(D)J recombination at the γδ and αβ TCR loci. Vγ3/Vδ1 T cells are the first TCR-bearing cells to arise in the fetal thymus and selectively home to the skin between embryonic day (ED) 16 and 18 (12, 13). It initially...

Dermal γδ T Cells Do Not Freely Re-Circulate Out of Skin and Produce IL-17 to Promote Neutrophil Infiltration during Primary Contact Hypersensitivity

“…Dermal γδ T cells have T effector memory phenotype (CD44 hi CD62L – ) and express the skin homing molecules --- E- and P-lig. Our previous studies had demonstrated that embryonic trafficking of DETC to skin is dependent on E-lig and CCR4 [21]. Interestingly, the majority of dermal γδ T cells also express CD69 and CD103 (S1B Fig), two molecules typically expressed by tissue resident memory T cells (T RM ) [20, 22–24].…”

“…Epidermis and dermis sheets were separated as previously described [21]. Briefly, ears were split into dorsal and ventral halves.…”

Aryl Hydrocarbon Receptor Is Critical for Homeostasis of Invariant γδ T Cells in the Murine Epidermis

“…Vg3/d1 T cells destined for the skin are generated and selected exclusively in the fetal thymus between embryonic days 15 and 18 (7,(21)(22)(23), and then migrate to the skin in an E/P selectindependent fashion (24), where they remain for life. In Vd 2/2 mice, ab TCR + DETC seed the skin, but disappear with time (17), suggesting that the epidermal niche for T cells cannot be successfully occupied by conventional T cells.…”

Embryonic Fate Mapping Uncovers the Critical Role of microRNAs in the Development of Epidermal γδ T Cells

“…The upregulation of a few key receptors on thymic Vγ3 + γδ T cells is critical for their epidermis homing (e.g., CCR10 and S1P1) and maintenance (e.g., CCR4) (Jiang et al, 2010; Jin et al, 2010; Nakamura et al, 2013; Xiong et al, 2004). Thus, we further examined the expression of these DETC homing/maintenance-associated molecules.…”