The costimulatory molecule ICOS promotes establishment of resident memory CD8+ T cells

Abstract Resident memory T cells (TRM) are critical for localized protective immunity in non-lymphoid tissues, but the signals involved in generating TRM are incompletely defined. Inducible T-cell costimulator (ICOS) is a costimulatory molecule expressed on activated T cells, and is highly expressed on TRM compared to recirculating memory CD8+ T cell subsets. While the role of ICOS has been well elaborated in T follicular helper cells, its function in CD8+ T cells is largely unexplored. Using both mixed bone-marrow chimeras and adoptive co-transfer of antigen-specific CD8+ T cells with acute infection models, we found ICOS deficient CD8+ T cells showed minimal defects in the initial effector expansion and the generation of recirculating memory population. However, consistent with its expression pattern, ICOS deficiency significantly compromised the establishment of CD8+ TRM cells in diverse non-lymphoid tissues. We further confirmed that the interaction between ICOS ligand (ICOSL) and ICOS is essential for CD8+ T cells tissue residency, and the defect of Icos−/− CD8+ T cells tissue residency can be detected even at early time points post infection, indicating that ICOS signaling affects initial retention of activated CD8+ T cells in non-lymphoid tissues. To gain a better understanding of the ICOS signaling, we used shRNA to knockdown KLF2, a transcription factor that we showed previously inhibits generation of CD8+ TRM and which is negatively regulated by ICOS stimulation in CD4+ Tfh. Our data support the model that ICOS-mediated down-regulation of KLF2 is important for the establishment of CD8+ TRM. Further investigations into the mechanistic basis by which ICOS signaling promotes CD8+ T cells tissue residency are ongoing.