Skin and heart allograft rejection solely by long-lived alloreactive T(RM) cells in skin of severe combined immunodeficient mice

Whether induced tissue-resident memory T (T(RM)) cells in nonlymphoid organs alone can mediate allograft rejection is unknown. By grafting alloskin or heart into severe combined immunodeficient or Rag2KO mice in which a piece of induced CD4(+) and/or CD8(+) T(RM) cell–containing MHC-matched or syngeneic skin was transplanted in advance, we addressed this issue. The induced CD4(+) T(RM) cells in the skin alone acutely rejected alloskin or heart grafts. RNA-seq analysis showed that induced CD4(+) T(RM) cells in skin favorably differentiated into T(H)17-like polarization during the secondary immune response. Inhibition of the key T(H)17 signaling molecule RORγt attenuated T(RM) cell–mediated graft rejection. Thus, we offer a unique mouse model to specifically study T(RM) cell–mediated allograft rejection without the involvement of lymphocytes in lymphoid organs and tissues. Our study provides strong evidence supporting the hypothesis that long-lived alloreactive T(RM) cells resident in other organs/tissues substantially contribute to organ allograft rejection.