Tissue-resident lymphocytes: from adaptive to innate immunity

Abstract

Efficient immune responses against invading pathogens often involve coordination between cells from both the innate and adaptive immune systems. For multiple decades, it has been believed that CD8⁺ memory T cells and natural killer (NK) cells constantly and uniformly recirculate. Only recently was the existence of noncirculating memory T and NK cells that remain resident in the peripheral tissues, termed tissue-resident memory T (T_RM) cells and tissue-resident NK (trNK) cells, observed in various organs owing to improved techniques. T_RM cells populate a wide range of peripheral organs, including the skin, sensory ganglia, gut, lungs, brain, salivary glands, female reproductive tract, and others. Recent findings have demonstrated the existence of T_RM in the secondary lymphoid organs (SLOs) as well, leading to revision of the classic theory that they exist only in peripheral organs. trNK cells have been identified in the uterus, skin, kidney, adipose tissue, and salivary glands. These tissue-resident lymphocytes do not recirculate in the blood or lymphatic system and often adopt a unique phenotype that is distinct from those of circulating immune cells. In this review, we will discuss the recent findings on the tissue residency of both innate and adaptive lymphocytes, with a particular focus on CD8⁺ memory T cells, and describe some advances regarding unconventional T cells (invariant NKT cells, mucosal-associated invariant T cells (MAIT), and γδ T cells) and the emerging family of trNK cells. Specifically, we will focus on the phenotypes and functions of these subsets and discuss their implications in anti-viral and anti-tumor immunity.

Keywords: Cancer; Tissue-resident NK cell; Tissue-resident memory T cell; Viral infection.

Fig. 1

Differentiation, maintenance, and function of T_RM cells. Naïve T cells are activated and transform into KLRG1⁻T_RM precursor cells. KLRG1⁻ T_RM precursor cells stop migrating immediately after pathogen clearance and begin to differentiate into T_RM cells with phenotypic markers of residence, which often results from the differential effects of transcription factors, cytokines, chemokines, and cognate antigen stimulation. Recirculating memory T cells and pre-existing T_RM cells give rise to secondary T_RM cells upon restimulation. Activated T_RM cells are involved in a variety of effector functions, including cytolytic activity, the secretion of proinflammatory cytokines such as IFN-γ and TNF-α, and the recruitment of other adaptive and innate immune cells