Skin and heart allograft rejection solely by long-lived alloreactive TRM cells in skin of severe combined immunodeficient mice

Qianchuan Tian; Zhaoqi Zhang; Liang Tan; Fan Yang; Yanan Xu; Yinan Guo; Dong Wei; Changhong Wu; Peng Cao; Jiawei Ji; Wei Wang; Xubiao Xie; Yong Zhao

doi:10.1126/sciadv.abk0270

Skin and heart allograft rejection solely by long-lived alloreactive T_RM cells in skin of severe combined immunodeficient mice

Sci Adv. 2022 Jan 28;8(4):eabk0270. doi: 10.1126/sciadv.abk0270. Epub 2022 Jan 26.

Authors

Qianchuan Tian^{1

2}, Zhaoqi Zhang^{1

2}, Liang Tan³, Fan Yang^{1

2}, Yanan Xu^{1

2}, Yinan Guo¹, Dong Wei^{1

2}, Changhong Wu^{1

2}, Peng Cao⁴, Jiawei Ji⁴, Wei Wang⁴, Xubiao Xie³, Yong Zhao^{1

2

5}

Affiliations

¹ State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
² University of Chinese Academy of Sciences, Beijing, China.
³ Department of Urological Organ Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China.
⁴ Department of Urology, Capital Medical University Beijing Chaoyang Hospital, Beijing, China.
⁵ Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.

Abstract

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_H17-like polarization during the secondary immune response. Inhibition of the key T_H17 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.