Tissue-resident memory T cells

Abstract

Tissue-resident memory T (Trm) cells constitute a recently identified lymphocyte lineage that occupies tissues without recirculating. They provide a first response against infections reencountered at body surfaces, where they accelerate pathogen clearance. Because Trm cells are not present within peripheral blood, they have not yet been well characterized, but are transcriptionally, phenotypically, and functionally distinct from recirculating central and effector memory T cells. In this review, we will summarize current knowledge of Trm cell ontogeny, regulation, maintenance, and function and will highlight technical considerations for studying this population.

Figure 1. T Cell Migration Patterns

T cell subsets exhibit distinct migration patterns. Like naive T cells, Tcm cells recirculate between blood, the T cell zones of secondary lymphoid organs, and lymph. Tem cells recirculate between nonlymphoid tissues, lymph, lymph nodes (where they might pass through via the sinuses, without entering the T cell zone), and blood. Trm CD8 cells do not recirculate but rather are confined to a single tissue.

Figure 2. Memory T Cell Differentiation

Like Tcm cells, Trm cells derive from KLRG1⁻ precursors in mice and are less terminally differentiated. However, Trm cell differentiation is regulated by local factors at sites of residence. KLRG1⁺ cells likely received more stimulation, are more terminally differentiated, and are capable of differentiating into Tem, but not Trm cells. High amounts of cell division, inflammatory cytokines, and antigen exposure ultimately result in T cell death or functional exhaustion.

Figure 3. Mechanisms of Memory T Cell Residence and Recirculation

Trm cells express low levels of the transcription factor KLF2 and S1PR1 and high levels of the C-type lectin CD69, which collectively prevent exit from the tissue. Certain Trm populations within mucosal or epidermal epithelium require αeβ7 integrin for maintenance (αe is also referred to as CD103). Trm cells are sometimes densely clustered in leukocyte aggregates that also contain myeloid cells. In contrast, recirculating Tem cells enter tissues from blood (typically from postcapillary venules) and express high amounts of KLF2 and S1PR1, but do not express CD69, which allows them to emigrate via S1P⁺ draining afferent lymphatics. Presentation on lymphatic endothelium of CCR7 ligands, CCL19 and CCL21, might also promote egress of CCR7⁺ non-lymphoid T cells.