The precursors of CD8+ tissue resident memory T cells: from lymphoid organs to infected tissues

Abstract

CD8⁺ tissue resident memory T cells (T_RM cells) are essential for immune defence against pathogens and malignancies, and the molecular processes that lead to T_RM cell formation are therefore of substantial biomedical interest. Prior work has demonstrated that signals present in the inflamed tissue micro-environment can promote the differentiation of memory precursor cells into mature T_RM cells, and it was therefore long assumed that T_RM cell formation adheres to a 'local divergence' model, in which T_RM cell lineage decisions are exclusively made within the tissue. However, a growing body of work provides evidence for a 'systemic divergence' model, in which circulating T cells already become preconditioned to preferentially give rise to the T_RM cell lineage, resulting in the generation of a pool of T_RM cell-poised T cells within the lymphoid compartment. Here, we review the emerging evidence that supports the existence of such a population of circulating T_RM cell progenitors, discuss current insights into their formation and highlight open questions in the field.

Fig. 1. Models of T_RM cell lineage divergence.

Branching of the CD8⁺ tissue resident memory T cell (T_RM cell) lineage from the circulating T cell lineages can be explained by two models. a | The tissue divergence model postulates that memory precursors within the circulation are equal in their potential to give rise to CD8⁺ circulating memory T cells (T_CIRCM cells) and T_RM cells. Only upon reaching the tissue do cells undergo changes that skew them towards the T_RM cell lineage, whereas those memory precursor T cells that remain in circulation start to differentiate into T_CIRCM cell lineages. b | The systemic divergence model postulates the existence of memory precursors within the circulating T cell pool that are poised to produce the T_RM cell lineage and these cells are superior in giving rise to T_RM cells relative to other circulating memory precursors. Note that these models do not address whether a fraction of cells with reduced T_RM cell-forming potential enter the tissue and later rejoin the circulation.

Fig. 2. Properties of T_RM cell-poised T cells.

Two properties endow CD8⁺ tissue resident memory T cell (T_RM cell)-poised T cells with an enhanced capacity to form T_RM cells. a | T_RM cell-poised memory precursor cells are more prone to enter non-lymphoid tissues (NLTs) and are well equipped to persist within this tissue, compared with other T cells. b | T_RM cell-poised memory precursor cells are more sensitive to signals, such as IL-15 and TGFβ, that drive T_RM cell differentiation within inflamed tissues, and thus more readily give rise to mature T_RM cells than other T cells that reach the tissue micro-environment.

Fig. 3. Signals within lymphoid tissues that poise T cells towards T_RM cell development.

Overview of signals within lymphoid tissues that affect the ability of T cells to form CD8⁺ tissue resident memory T cells (T_RM cells) in mouse models. Prior to antigen encounter, naive T cells require periodic TGFβ signalling to adopt and retain a T_RM cell-poised state. Upon infection, priming by BATF3⁺ dendritic cells, which provide IL-15, IL-12 and CD24 signalling, biases T cells to form T_RM cells. Presence of tissue-derived factors, such as derivatives of vitamin A and vitamin D, during priming can stimulate the expression of tissue-specific homing molecules, thereby guiding T_RM cell-poised T cells to the relevant affected tissues. The presence of TGFβ during priming further maintains the T_RM cell-poised state, and it may be proposed that in the absence of TGFβ, T cells primed by BATF3⁺ dendritic cells are prone to give rise to the CD8⁺ effector memory T cell (T_EM cell) and terminal effector T cell lineages. T_CM cell, CD8⁺ central memory T cell.

Fig. 4. Distinguishing characteristics of T_RM cell-poised memory precursor cells within the circulation.

Circulating CD8⁺ tissue resident memory T cell (T_RM cell)-poised and CD8⁺ circulating memory T cell (T_CIRCM cell)-poised memory precursor T cells share the classical memory precursor phenotype IL-7Rα^hiKLRG1^low. However, numerous other properties could be used to distinguish the two groups of memory precursor cells^,,,. Arrows depict relative level of activity or expression. Data on BLIMP1 and RUNX3 are indirect.