Search

Regulatory T cells (T regs ) are present in lymphoid and nonlymphoid tissues where they restrict immune activation, prevent autoimmunity, and regulate inflammation. T regs in nonlymphoid tissues are typically resident, whereas those in lymph nodes (LNs) are considered to recirculate. However, T regs in LNs are not a homogenous population, and circulation kinetics of different T reg subsets are poorly characterized. Furthermore, whether T regs can acquire memory T cell properties and persist for extended periods after their activation in LNs is unclear. Here, we used in situ labeling with a stabilized photoconvertible protein to uncover turnover rates of T regs in LNs in vivo. We found that, whereas most T regs in LNs recirculate, 10 to 20% are memory-like resident cells that remain in their respective LNs for weeks to months. Single-cell RNA sequencing revealed that LN-resident cells are a functionally and ontogenetically heterogeneous population and share the same core residency gene signature with conventional CD4 + and CD8 + T cells. Resident cells in LNs did not actively proliferate and did not require continuous T cell receptor (TCR) signaling for their residency. However, resident and circulating T regs had distinct TCR repertoires, and each LN contained exclusive clonal subpopulations of resident T regs . Our results demonstrate that, similar to conventional T cells, T regs can form resident memory-like populations in LNs after adaptive immune responses. Specific and local suppression of immune responses by resident T regs in draining LNs might provide previously unidentified therapeutic opportunities for the treatment of local chronic inflammatory conditions.

Group 1 innate lymphoid cells (ILCs) comprising circulating natural killer (cNK) cells and tissue-resident ILC1s are critical for host defense against pathogens and tumors. Despite a growing understanding of their role in homeostasis and disease, the ontogeny of group 1 ILCs remains largely unknown. Here, we used fate mapping and single-cell transcriptomics to comprehensively investigate the origin and turnover of murine group 1 ILCs. Whereas cNK cells are continuously replaced throughout life, we uncovered tissue-dependent development and turnover of ILC1s. A first wave of ILC1s emerges during embryogenesis in the liver and transiently colonizes fetal tissues. After birth, a second wave quickly replaces ILC1s in most tissues apart from the liver, where they layer with embryonic ILC1s, persist until adulthood, and undergo a specific developmental program. Whereas embryonically derived ILC1s give rise to a cytotoxic subset, the neonatal wave establishes the full spectrum of ILC1s. Our findings uncover key ontogenic features of murine group 1 ILCs and their association with cellular identities and functions.

Group 1 innate lymphoid cells (ILCs), which comprise both natural killer (NK) cells and ILC1s, are important innate effectors that can also positively and negatively influence adaptive immune responses. The latter function is generally ascribed to the ability of NK cells to recognize and kill activated T cells. Here, we used multiphoton intravital microscopy in mouse models of hepatitis B to study the intrahepatic behavior of group 1 ILCs and their cross-talk with hepatitis B virus (HBV)-specific CD8 + T cells. We found that hepatocellular antigen recognition by effector CD8 + T cells triggered a prominent increase in the number of hepatic NK cells and ILC1s. Group 1 ILCs colocalized and engaged in prolonged interactions with effector CD8 + T cells undergoing hepatocellular antigen recognition; however, they did not induce T cell apoptosis. Rather, group 1 ILCs constrained CD8 + T cell proliferation by controlling local interleukin-2 (IL-2) availability. Accordingly, group 1 ILC depletion, or genetic removal of their IL-2 receptor a chain, considerably increased the number of intrahepatic HBV-specific effector CD8 + T cells and the attendant immunopathology. Together, these results reveal a role for group 1 ILCs in controlling T cell-mediated liver immunopathology by limiting local IL-2 concentration and have implications for the treatment of chronic HBV infection.