CD8+ Tissue-Resident Memory T Cells: Versatile Guardians of the Tissue

Abstract

Tissue-resident memory T (Trm) cells are a subset of T cells maintained throughout life within nonlymphoid tissues without significant contribution from circulating memory T cells. CD8+ Trm cells contribute to both tissue surveillance and direct elimination of pathogens through a variety of mechanisms. Reactivation of these Trm cells during infection drives systematic changes within the tissue, including altering the state of the epithelium, activating local immune cells, and contributing to the permissiveness of the tissue for circulating immune cell entry. Trm cells can be further classified by their functional outputs, which can be either subset- or tissue-specific, and include proliferation, tissue egress, and modulation of tissue physiology. These functional outputs of Trm cells are linked to the heterogeneity and plasticity of this population, and uncovering the unique responses of different Trm cell subsets and their role in immunity will allow us to modulate Trm cell responses for optimal control of disease.

Figure 1.. Trm cells are versatile and adaptable.

A. Trms possess diverse and effective mechanisms that amplify the local immune response, stratified by tissue of residence. B. Trm cells are flexible in their function and/or phenotype in a context-dependent manner, with capacity to adapt to specific infection circumstances to optimize immune responses. These adaptations include: (1) Functional plasticity. Some Trm cells that produce pro-inflammatory cytokines can also shift to release wound-repair factors upon sensing alarmins. (2) Phenotypic flexibility. Trm cells can upregulate the expression of cell surface markers during secondary challenge and adjust their function. (3) Tissue adaptability. Trm cells are able to exit the tissue and migrate into draining and proximal lymph nodes, where they may acquire residency and support the increase of local responses to infection. NLT: non-lymphoid tissue.

Figure 2.. Small intestinal Trm cells illustrate the concept of intra-tissue phenotypic and functional diversity.

At steady state, peripheral non-lymphoid tissues exhibit intra-tissue phenotypic heterogeneity of the CD8⁺ Trm compartment. Upon pathogen or peptide rechallenge, reactivation of the heterogenous pools of Trm cells reveals a division of labor between these populations. Here we present CD8⁺ Trm cells of the small intestine as an illustration of this concept. Intraepithelial (IEL) Trms are uniformly CD69⁺CD103⁺, however can be divided by the differential expression of Id3, which will determine their functional properties during secondary responses. IEL Id3⁺ Trms display elevated potential for cytokine production compared to those Id3⁻. In the lamina propria (LP), CD69⁺ Trms show a dichotomy based on the cell surface expression of CD103, where at steady state CD103⁺ Trm cells are patrolling the base of the epithelium and those CD103⁻ are frequently in proximity to CD11c⁺ dendritic cells (DCs). Upon antigen re-encounter, CD103⁻ Trms are more proliferative and produce proinflammatory cytokines that prompt recruitment and increase infiltration of other circulating CD8⁺ memory T cells as well as innate monocytes and neutrophils. On the other hand, CD103⁺ LP Trms undergo robust bystander activation in response to pathogen-generated inflammation.