Tissue resident memory T cells and viral immunity

Abstract

Tissue resident memory T cells (T_RM) constitute a recently identified T cell lineage that is responsible for frontline defense against viral infections. In contrast to central and effector memory T cells, which constitutively recirculate between tissues and blood, T_RM reside permanently within tissues. As the main surveyors of non-lymphoid tissues, T_RM are positioned to rapidly respond upon reinfection at barrier sites. During a viral reinfection, T_RM trigger the local tissue environment to activate and recruit immune cells and establish an antiviral state. Consistent with this function, there is empirical evidence that T_RM accelerate control in the event of reinfection or possible reactivation of latent infections in solid organs and barrier tissues. Here we review recent literature highlighting the protective functions of T_RM in multiple viral challenge models and contextualize the implications of these findings for vaccine development.

Figure 1. Patterns of memory T cell migration

Memory T cells are parsed into subsets that have different migration patterns. The prevailing model is described here. Central memory T cell (T_CM) migration is similar to that of naïve T cells and emphasizes immunosurveillance of secondary lymphoid organs (SLOs, such as lymph nodes, intestinal Peyer’s patches, and the white pulp of spleen). Specifically, T_CM migrate from blood into SLOs, exit via lymphatic vessels, then rejoin the blood supply to being this recirculation pattern anew. Effector memory T cells (T_EM) recirculate through blood, nonlymphoid tissue (NLT), then back into the blood via the lymph (while transiently passing through SLOs). Tissue resident memory cells (T_RM) are parked within tissues and do not recirculate. Studies indicating that T_RM may dominate immunosurveillance of NLTs have exposed gaps in our understanding of bona fide T cell recirculation through these compartments.

Figure 2. Broad evidence that T_RM accelerate viral control upon rechallenge

This figure summarizes several mouse studies demonstrating that T_RM can protect a wide array of tissues against many viral challenges.

Figure 3. CD8+ T_RM functions

Some CD8+ T_RM express high basal levels of granzyme B suggesting reactivated T_RM may be constitutively poised to kill infected cells, although this has not been formally tested in vivo. Upon recognition of cognate antigen, T_RM also secrete pro-inflammatory cytokines, namely IFNγ, IL-2 and TNFα, which act to upregulate chemokines such as CXCL9 and CXCL10, as well the adhesion molecule VCAM-1 on endothelial cells. This facilitates recruitment of recirculating subsets of memory CD8+ T cells and B cells into the tissue. Interferon stimulated genes (ISGs) are also upregulated in cells surrounding reactivated T_RM which may increase their resistance to viral infection. Furthermore, recognition of viral antigen by T_RM also precipitates upregulation of granzyme B by natural killer cells (NK) and bystander memory CD8+ T cells and maturation of local dendritic cells (DCs). In summary, T_RM trigger a cascade of immunostimulatory and antiviral responses at sites of viral re-exposure.