Epidermis instructs skin homing receptor expression in human T cells

Abstract

The localization of memory T cells to human skin is essential for long-term immune surveillance and the maintenance of barrier integrity. Although the mechanisms controlling memory T-cell migration to peripheral tissues are poorly understood, the current paradigm includes the localized secretion of "imprinting" signals from tissue-resident dendritic cells in the draining lymph nodes. Here we show that CCR8 expression by newly activated naive T cells is regulated by skin-specific factor(s) derived primarily from epidermal keratinocytes, thereby providing a mechanism for the preferential expression of CCR8 by skinresident memory T cells. Importantly, no such effects were observed after coculture with primary cells from skin-unrelated epithelia, including mesothelium and small intestine. The keratinocyte-derived CCR8-inducing factor(s) were soluble, and independent of vitamins A and D. Furthermore, the induction of CCR8 under these conditions correlated with an increase in cutaneous lymphocyte-associated antigen expression. Our findings challenge current tissue homing paradigms, especially those involving CCR10, and emphasize the importance of steady-state epidermis rather than tissue-resident dendritic cells in controlling the localization of memory T cells within human skin. (Blood. 2012;120(23):4591-4598) IntroductionThe majority of lymphocytes reside in peripheral tissues, where they fulfill essential immune surveillance functions. 1 Peripheral tissue immune surveillance T cells (T PS ) are antigen-experienced sentinels that provide first-line defense against recurrent infections and are thought to control aberrant autoimmunity. 2 Early work in animal models provided clear evidence for the presence of tissue tropism in memory T cells that correlated with the site of infection or vaccine deposition. 3,4 In contrast to effector T cells, which are short-lived and can traffic to multiple unrelated sites, 5 such memory T cells persist in peripheral tissues long after resolution of the primary immune response, 1 exist in disequilibrium with circulating blood T cells, 6,7 and provide protection against reinfection in both mice and humans. [6][7][8][9][10] The mechanisms underlying the segregation of memory T cells to distinct, nonoverlapping sites are not well understood but appear to depend on the coordinated expression of specific adhesion molecules and chemokine receptors. Understanding this process is essential for the development of rational vaccination strategies and requires the processing of tissue samples from healthy peripheral organs.Recent studies have implicated vitamins A and D in the control of T-cell homing to the small intestine and skin tissue. 11,12 In brief, vitamin A was shown to play a crucial role in the induction of the "gut-homing" receptors CCR9 and ␣4␤7 in murine T cells, 13 and the production of active vitamin A metabolites was shown to be a feature of local CD103 ϩ dendritic cells (DCs), [14][15][16] findings that were subsequently replicated with human T cells. 14,17 The situation for ski...

Safety, Immunogenicity, and Antibody Persistence following an Investigational Streptococcus pneumoniae and Haemophilus influenzae Triple-Protein Vaccine in a Phase 1 Randomized Controlled Study in Healthy Adults

“…This may indicate that, rather than circulating in the bloodstream, inactive memory T cells were sequestrated in lymphoid tissue prior to stimulation by vaccination. Indeed, evidence for the presence of specific T-cell homing receptors may mean that T cells boosted by vaccination may have exited the circulation prior to blood sampling (41). Some T-cell responses, including Th17 responses, are known to be short lived (42).…”

Mucosal immunity and novel tuberculosis vaccine strategies: route of immunisation-determined T-cell homing to restricted lung mucosal compartments

“…Extensive evidence demonstrates the ability of local dendritic cell populations to influence the migration of T-cells to the gut and skin [22][23][24][25]. Whether this also holds true for T-cell migration to the respiratory tract is less clear.…”

Fine-Needle Aspiration Biopsy of the Lymph Node: A Novel Tool for the Monitoring of Immune Responses after Skin Antigen Delivery

“…They are predominantly CD45RA 2 CCR7 2 effector memory cells, but there is a proportion of CLA + CCR7 + cells, which are known as "central memory skin homing cells" that can enter the skin but most likely have access to the LNs as well (5). A subpopulation of CD45RA 2 CCR7 2 cells, also called peripheral tissue immune surveillance T cells, express CCR8, which regulates their localization in the skin during steady state, whereas other skin homing markers, such as CCR4 and CCR10, are largely responsible for the localization of activated T cells during immune responses (10).…”