Local immunity by tissue-resident CD8(+) memory T cells

Abstract

Microbial infection primes a CD8(+) cytotoxic T cell response that gives rise to a long-lived population of circulating memory cells able to provide protection against systemic reinfection. Despite this, effective CD8(+) T cell surveillance of barrier tissues such as skin and mucosa typically wanes with time, resulting in limited T cell-mediated protection in these peripheral tissues. However, recent evidence suggests that a specialized subset of CD103(+) memory T cells can permanently lodge and persist in peripheral tissues, and that these cells can compensate for the loss of peripheral immune surveillance by circulating memory T cells. Here, we review evolving concepts regarding the generation and long-term persistence of these tissue-resident memory T cells (T(RM)) in epithelial and neuronal tissues. We further discuss the role of T(RM) cells in local infection control and their contribution to localized immune phenomena, in both mice and humans.

Keywords: T cell; memory; periphery; protection; virus infection.

Figure 1

Local differentiation and persistence of T_RM cells. (A) Localized infection or inflammation of the skin generates a population of epidermal CD103⁺ T_RM cells that exist in disequilibrium with their counterparts in the circulation. High numbers of T_RM cells are concentrated at sites of previous infection or inflammation, whereas remote areas of skin contain only low numbers of these cells. (B) Effector CD8⁺ T cells that have infiltrated infected skin can undergo three principal fates. While the majority of cells are likely to (i) die in situ, others may (ii) egress the skin in a CCR7-depdendent fashion and join the evolving pool of circulating memory T cells. A minority of cells may (iii) access the epidermal layer of the skin where they can undergo TGF-β-dependent differentiation into T_RM cells during the resolution phase of infection. (C) The role of local antigen recognition in T_RM-differentiation is dependent on anatomical location. While peripheral tissues such as skin and intestinal mucosa can promote T_RM-differentiation in the absence of local antigenic stimulation, the same process in neuronal tissues such as brain and ganglia requires local antigenic T cell restimulation. The basement membrane in the skin and the blood-brain-barrier in the brain sequester T_RM cells from the circulation.

Figure 2

Local immunity by site-specific or global lodgment of T_RM cells. (A) High numbers of T_RM cells can be generated in the skin by an immunization strategy that combines the induction of effector T cells with the local application of an inflammatory stimulus. This results in potent local immunity at the targeted site. (B) Repeated immunizations in different skin sites result in elevated numbers of T_RM cells in both targeted and remote areas of skin. This strategy has the potential to generate global T_RM-cell-mediated immunity against skin infection, although this remains to be formally proven.