Resident memory T cells (T_RM cells) are an important first-line defense against respiratory pathogens, but the unique contributions of lung T_RM cell populations to protective immunity and the factors that govern their localization to different compartments of the lung are not well understood. Here, we show that airway and interstitial T_RM cells have distinct effector functions and that CXCR6 controls the partitioning of T_RM cells within the lung by recruiting CD8 T_RM cells to the airways. The absence of CXCR6 significantly decreases airway CD8 T_RM cells due to altered trafficking of CXCR6^−/− cells within the lung, and not decreased survival in the airways. CXCL16, the ligand for CXCR6, is localized primarily at the respiratory epithelium, and mice lacking CXCL16 also had decreased CD8 T_RM cells in the airways. Finally, blocking CXCL16 inhibited the steady-state maintenance of airway T_RM cells. Thus, the CXCR6/CXCL16 signaling axis controls the localization of T_RM cells to different compartments of the lung and maintains airway T_RM cells.

CD8+ tissue-resident memory T cells (TRM cells) reside permanently in nonlymphoid tissues and provide a first line of protection against invading pathogens. However, the precise localization of CD8+ TRM cells in the lung, which physiologically consists of a markedly scant interstitium compared with other mucosa, remains unclear. In this study, we show that lung CD8+ TRM cells localize predominantly in specific niches created at the site of regeneration after tissue injury, whereas peripheral tissue-circulating CD8+ effector memory T cells (TEM cells) are widely but sparsely distributed in unaffected areas. Although CD69 inhibited sphingosine 1–phosphate receptor 1–mediated egress of CD8+ T cells immediately after their recruitment into lung tissues, such inhibition was not required for the retention of cells in the TRM niches. Furthermore, despite rigid segregation of TEM cells from the TRM niche, prime-pull strategy with cognate antigen enabled the conversion from TEM cells to TRM cells by creating de novo TRM niches. Such damage site–specific localization of CD8+ TRM cells may be important for efficient protection against secondary infections by respiratory pathogens.

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.

Immunotherapy targeting programmed cell death-1 (PD-1) induces durable antitumor efficacy in many types of cancer. However, such clinical benefit is limited because of the insufficient reinvigoration of antitumor immunity with the drug alone; therefore, rational therapeutic combinations are required to improve its efficacy. In our preclinical study, we evaluated the antitumor effect of U3-1402, a human epidermal growth factor receptor 3–targeting (HER3–targeting) antibody-drug conjugate, and its potential synergism with PD-1 inhibition. Using a syngeneic mouse tumor model that is refractory to anti–PD-1 therapy, we found that treatment with U3-1402 exhibited an obvious antitumor effect via direct lysis of tumor cells. Disruption of tumor cells by U3-1402 enhanced the infiltration of innate and adaptive immune cells. Chemotherapy with exatecan derivative (Dxd, the drug payload of U3-1402) revealed that the enhanced antitumor immunity produced by U3-1402 was associated with the induction of alarmins, including high-mobility group box-1 (HMGB-1), via tumor-specific cytotoxicity. Notably, U3-1402 significantly sensitized the tumor to PD-1 blockade, as a combination of U3-1402 and the PD-1 inhibitor significantly enhanced antitumor immunity. Further, clinical analyses indicated that tumor-specific HER3 expression was frequently observed in patients with PD-1 inhibitor–resistant solid tumors. Overall, U3-1402 is a promising candidate as a partner of immunotherapy for such patients.

Populations of CD8⁺ lung-resident memory T (T_RM) cells persist in the interstitium and epithelium (airways) following recovery from respiratory virus infections. While it is clear that CD8⁺ T_RM cells in the airways are dynamically maintained via the continuous recruitment of new cells, there is a vigorous debate about whether tissue-circulating effector memory T (T_EM) cells are the source of these newly recruited cells. Here we definitively demonstrate that CD8⁺ T_RM cells in the lung airways are not derived from T_EM cells in the circulation, but are seeded continuously by T_RM cells from the lung interstitium. This process is driven by CXCR6 that is expressed uniquely on T_RM cells but not T_EM cells. We further demonstrate that the lung interstitium CD8⁺ T_RM cell population is also maintained independently of T_EM cells via a homeostatic proliferation mechanism. Taken together, these data show that lung memory CD8⁺ T_RM cells in the lung interstitium and airways are compartmentally separated from T_EM cells and clarify the mechanisms underlying their maintenance.

Respiratory virus infections, such as those mediated by influenza virus, parainfluenza virus, respiratory syncytial virus (RSV), severe acute respiratory syndrome coronavirus (SARS-CoV), rhinovirus, and adenovirus, are responsible for substantial morbidity and mortality, especially in children and older adults. Furthermore, the potential emergence of highly pathogenic strains of influenza virus poses a significant public health threat. Thus, the development of vaccines capable of eliciting long-lasting protective immunity to those pathogens is a major public health priority. CD8⁺ Tissue-resident memory T (T_RM) cells are a newly defined population that resides permanently in the nonlymphoid tissues including the lung. These cells are capable of providing local protection immediately after infection, thereby promoting rapid host recovery. Recent studies have offered new insights into the anatomical niches that harbor lung CD8⁺ T_RM cells, and also identified the requirement and limitations of T_RM maintenance. However, it remains controversial whether lung CD8⁺ T_RM cells are continuously replenished by new cells from the circulation or permanently lodged in this site. A better understanding of how lung CD8⁺ T_RM cells are generated and maintained and the tissue-specific factors that drive local T_RM formation is required for optimal vaccine development. This review focuses on recent advance in our understanding of CD8⁺ T_RM cell establishment and maintenance in the lung, and describes how those processes are uniquely regulated in this tissue.