The Human Cutaneous Chemokine System

Abstract

Irrespective of the immune status, the vast majority of all lymphocytes reside in peripheral tissues whereas those present in blood only amount to a small fraction of the total. It has been estimated that T cells in healthy human skin outnumber those present in blood by at least a factor of two. How lymphocytes within these two compartments relate to each other is not well understood. However, mounting evidence suggest that the study of T cell subsets present in peripheral blood does not reflect the function of their counterparts at peripheral sites. This is especially true under steady-state conditions whereby long-lived memory T cells in healthy tissues, notably those in epithelial tissues at body surfaces, are thought to fulfill a critical immune surveillance function by contributing to the first line of defense against a series of local threats, including microbes, tumors, and toxins, and by participating in wound healing. The relative scarcity of information regarding peripheral T cells and the factors regulating their localization is primarily due to inherent difficulties in obtaining healthy tissue for the extraction and study of immune cells on a routine basis. This is most certainly true for humans. Here, we review our current understanding of T cell homing to human skin and compare it when possible with gut-selective homing. We also discuss candidate chemokines that may account for the tissue selectivity in this process and present a model whereby CCR8, and its ligand CCL1, selectively regulate the homeostatic migration of memory lymphocytes to skin tissue.

Epidermis instructs skin homing receptor expression in human T cells

“…CCR8 expression in human blood leukocytes is scarce and largely restricted to central and effector memory ␣␤ T cells 25,28,29 ( Figure 1A-B), despite previous reports claiming a broader distribution (reviewed by McCully and Moser 24 ). In agreement with our earlier studies, 23,30 we found that CCR8 is preferentially expressed on T cells present in healthy human skin (49.5% Ϯ 5.8%; n ϭ 7; Figure 1A) compared with those present in blood (5.05% Ϯ 1.53%; n ϭ 14), and have a predominant effector memory (CD45RA Ϫ CCR7 Ϫ ) phenotype, although for some donors a significant fraction of CD8 ϩ T cells were terminally differentiated as characterized by CD45RA re-expression (Temra; Figure 1B).…”

“…19,20 Our findings support a model that places healthy skin tissue at the helm of skin-tropic T PS regulation. 24 It moves the attention away from local DCs, which on their own are relatively poor inducers of CCR8, and emphasizes the role of stable soluble factor(s) produced by keratinocytes that act directly on activated T cells. We propose that drainage of these factor(s) together with antigen, either in free (unprocessed) form or captured by migrating DCs, into adjacent lymph nodes results in CCR8 and CLA expression in responding T cells.…”

“…23 These findings prompted us to suggest a role for the CCL1/CCR8 chemokine system in the control of cutaneous T PS cells. 24 Human blood CCR8 ϩ T cells are capable of producing IL-5, 25 but cytokine production by their skin counterparts has not been established. Here we provide direct evidence that epidermal tissue imprints skin tropism (CCR8 and CLA expression) during the activation of naive human T cells, thereby controlling the localization of skin-selective human T PS cells.…”

Location, Location, Location: The Impact of Migratory Heterogeneity on T Cell Function

“…CD43 and CD44 expressed by T cells can also act to engage E-selectin. Although many chemokines can participate in migration of effector T cells to the skin depending on the characteristics of the infection or inflammation (50), the capacity for recruitment of effector T cells to the skin is primarily associated with expression of CCR8 and CCR10. While skin T cells express high levels of CCR4 and its ligands CCL17 and CCL22 are produced by epidermal keratinocytes and dermal fibroblasts, skin DC have not been shown to imprint CCR4 expression, which suggests that this MR is not exclusively a skin-homing molecule.…”

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.…”