Niches for the Long-Term Maintenance of Tissue-Resident Memory T Cells

Tissue-resident memory T cells (T_RM cells) are a population of immune cells that reside in the lymphoid and non-lymphoid organs without recirculation through the blood. These important cells occupy and utilize unique anatomical and physiological niches that are distinct from those for other memory T cell populations, such as central memory T cells in the secondary lymphoid organs and effector memory T cells that circulate through the tissues. CD8⁺ T_RM cells typically localize in the epithelial layers of barrier tissues where they are optimally positioned to act as sentinels to trigger antigen-specific protection against reinfection. CD4⁺ T_RM cells typically localize below the epithelial layers, such as below the basement membrane, and cluster in lymphoid structures designed to optimize interactions with antigen-presenting cells upon reinfection. A key feature of T_RM populations is their ability to be maintained in barrier tissues for prolonged periods of time. For example, skin CD8⁺ T_RM cells displace epidermal niches originally occupied by γδ T cells, thereby enabling their stable persistence for years. It is also clear that the long-term maintenance of T_RM cells in different microenvironments is dependent on multiple tissue-specific survival cues, although the specific details are poorly understood. However, not all T_RM persist over the long term. Recently, we identified a new spatial niche for the maintenance of CD8⁺ T_RM cells in the lung, which is created at the site of tissue regeneration after injury [termed repair-associated memory depots (RAMD)]. The short-lived nature of RAMD potentially explains the short lifespans of CD8⁺ T_RM cells in this particular tissue. Clearly, a better understanding of the niche-dependent maintenance of T_RM cells will be important for the development of vaccines designed to promote barrier immunity. In this review, we discuss recent advances in our understanding of the properties and nature of tissue-specific niches that maintain T_RM cells in different tissues.