Securing front-line T cell defense.

Abstract

Lymphocytes are critical “moving parts” of the dynamic defense system protecting us from invading pathogens and internal enemies. A recent report from Milner et al. has pinpointed a way to position T lymphocytes at strategic locations in the body.1 This insight may ultimately improve our approaches to vaccination and cancer treatment. T cells patrol the body, by proxy, wandering from lymph node to lymph node until encountering evidence that a barrier has been breached or that a tissue has undergone malignant transformation. When selected T cell clones are presented evidence of “intrusion,” they undergo vigorous division and produce cellular descendants with heterogeneous differentiation fates (Figure 1). Cells that differentiate (effector cells) leave the lymph node to exert function in relevant tissues, and subsequently die. Memory T cells persist following control of infection and serve specialized functions.2 Less differentiated (central memory) cells recirculate through lymph nodes and upon rechallenge give rise to differentiated effector cells while self-renewing the central memory cell pool. Effector memory cells are typically more differentiated than central memory cells and circulate more widely, even passing through non-lymphoid tissues. Tissue-resident memory cells populate non-lymphoid tissues neither dying like bona fide effector cells nor recirculating like other memory cells. Tissue-resident memory cells thereby provide heightened defense in organs and barrier surfaces during recurrence of infections. The ontogeny of tissue-resident memory T cells is incompletely understood but the paper by Milner et al. provides important insight into the transcription factor network that governs the establishment and maintenance of tissue residence by CD8+ T cells.1 Conventionally, candidate transcription factors of lineage specification would be uniquely expressed in said lineage. Instead, Milner et al. used a discovery approach not requiring unique gene expression of a transcription factor for its candidacy. The authors exploited a Google-like algorithm that combines chromatin accessibility and gene expression data to predict key transcription factors, followed by validation of potential candidates using RNA interference. Milner et al. discovered that Runx3, a transcriptional regulator important in development and function of CD8+ T cells as well as intestinal tissue residence of CD4+ T cells is a key transcription factor for tissue-resident memory cell localization.1 Despite being expressed at relatively similar levels in all memory CD8+ T cells, genetic experiments indicated that Runx3 is necessary and sufficient for establishment and maintenance of non-lymphoid tissue residence by CD8+ memory T cells. In addition to promoting expression of genes associated with tissue residence and repressing genes associated with circulating memory cells, Runx3 also positively regulated cell survival and expression of Granzyme B in tissue-resident memory cells. Because tissue-resident memory cells share characteristics with tumor-infiltrating T cells, the authors used genetic approaches to test the role of Runx3 in cancer models.1 As observed in infectious disease models, Runx3 overexpression promoted tumor-infiltrating T cell abundance and tumor clearance, while loss of Runx3 was deleterious for T cell persistence in tumor and control of tumor burden. In human cancer specimens, Runx3 expression in tumor-infiltrating T cells correlated with the tissue-resident gene expression signature, suggesting that Runx3 may be an important biomarker as well a mode of immune enhancement in non-lymphoid tissues. The study by Milner et al. adds important and therapeutically relevant information about the establishment and maintenance of tissue residency among memory T cells. Some future questions regarding the roles of Runx3 in tissue-resident memory T cell biology will likely revolve around whether regulating the establishment of widespread tissue-resident memory cells following a systemic or disseminated infection will be similar to the rules governing establishment of focal tissue-resident memory cells following a localized infection. So far as two other key transcription factors, Blimp1 and its homolog, “Hobit,” act redundantly to specify tissue-resident memory T cell differentiation,3 it will also be of interest to determine what role Runx3 plays in the expression and function of those other transcription factors. Although we understand some features of how tissue-resident memory cells may arise early during clonal expansion,4 fundamental questions about tissue-resident memory cell longevity and/or long-term replenishment remain to be addressed. In view of the recent findings that durability of ongoing T cell responses depends on self-renewal of less differentiated progenitors that repeatedly give rise to more differentiated effector cells,5-10 it remains possible that heterogeneity among tissue-resident memory cells within a given tissue could be partly due to a precursor-product relationship. Whether replenishing tissue-resident memory cells might occur from periodic seeding by a memory cell precursor in circulation or in a lymphoid-like substructure within tissue will also require further investigation (Figure 1). Leveraging the capacity of memory T cells to take residence in non-lymphoid tissues for defense against infectious diseases and curtailing cancer growth is likely to become an increasingly exciting prospect for translational science and medicine.