Schneider Revueltas, E.; Almes, L.; Tokoyoda, K.; Deng, X.; Casanovas Subirana, A.; Ferreira-Gomes, M.; Cornelis, R.; Dong, J.; Heinrich, F.; Durek, P.; Mashreghi, M.-F.; Chang, H.-D.; Radbruch, A.

Persistence of memory T lymphocytes, in the apparent absence of antigen, is a hallmark of immune memory and key to adaptive immunity to recurrent infections. The signaling pathways ensuring survival and quiescence of the memory T cells are largely enigmatic. Here we show, by inhibition in vivo, that persistence of surface CD69+KLF2- tissue-resident memory T cells of murine bone marrow and spleen is blocked by antibodies to the integrins VLA-4 and LFA-1, connecting the memory T cells to VCAM and ICAM of stromal cells. Persistence requires the PI3K/AKT signaling pathway, since it is blocked by Wortmannin, and it involves PI3K-dependent survival genes. Surface CD69-KLF2+ memory T cells of the bone marrow are also dependent on integrin-mediated contact to stromal cells. Their persistence critically depends on the NFkB pathway, their PI3K signaling pathway is not relevant. Blocking Jak1 and 3 of the interleukin-7 and -15 signaling pathways does affect memory T cells of the spleen, but not those of the bone marrow. Thus tissue-resident KLF2+ and KLF2- memory T cells, and memory T cells of spleen and bone marrow use different signaling pathways, adapting them to their tissue of residency, and reflecting an unexpected heterogeneity of molecular mechanisms of persistence