Resident regulatory T cells reflect the immune history of individual lymph nodes

Abstract

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.