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.