Zou et al. demonstrated that naive alloantigen-specific CD4+ T cells mainly develop into TCF1+Ly108+ effector precursor (TEP) cells and TCF1−CXCR6+ effectors in response to heart transplantation. Adoptive transfer of TCF1+ stem-like CD4+ TEP cells, but not TCF1− CD4+ effector cells, induced transplant rejection. Mechanistically, TCF1 sustained the self-renewal potential of CD4+ TEP cells, while IRF4 governed their differentiation into effector cells. scRNAseq analysis further identified LDHA as a crucial regulator of CD4+ TEP cell differentiation. In the absence of IRF4 or LDHA, CD4+ TEP cells failed to differentiate into TCF1−CXCR6+ effector cells, leading to transplant acceptance.
Contributed by Shishir Pant
ABSTRACT: CD4(+) T cells are central to various immune responses, but the molecular programs that drive and maintain CD4(+) T cell immunity are not entirely clear. Here we identify a stem-like program that governs the CD4(+) T cell response in transplantation models. Single-cell-transcriptomic analysis revealed that naive alloantigen-specific CD4(+) T cells develop into TCF1(hi) effector precursor (T(EP)) cells and TCF1(-)CXCR6(+) effectors in transplant recipients. The TCF1(-)CXCR6(+)CD4(+) effectors lose proliferation capacity and do not reject allografts upon adoptive transfer into secondary hosts. By contrast, the TCF1(hi)CD4(+) T(EP) cells have dual features of self-renewal and effector differentiation potential, and allograft rejection depends on continuous replenishment of TCF1(-)CXCR6(+) effectors from TCF1(hi)CD4(+) T(EP) cells. Mechanistically, TCF1 sustains the CD4(+) T(EP) cell population, whereas the transcription factor IRF4 and the glycolytic enzyme LDHA govern the effector differentiation potential of CD4(+) T(EP) cells. Deletion of IRF4 or LDHA in T cells induces transplant acceptance. These findings unravel a stem-like program that controls the self-renewal capacity and effector differentiation potential of CD4(+) T(EP) cells and have implications for T cell-related immunotherapies.
Author Info: (1) Immunobiology & Transplant Science Center, Department of Surgery, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA. Organ Transplant Center, T
Author Info: (1) Immunobiology & Transplant Science Center, Department of Surgery, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA. Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. (2) Systems Medicine and Bioengineering Department, Houston Methodist Neal Cancer Center, Houston, TX, USA. Department of Radiology, Houston Methodist Hospital, Weill Cornell Medicine, Houston, TX, USA. (3) Department of Surgery, J. C. Walter Jr. Transplant Center, Houston Methodist Hospital, Houston, TX, USA. Department of Surgery, Weill Cornell Medicine, Cornell University, New York, NY, USA. (4) Immunobiology & Transplant Science Center, Department of Surgery, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA. (5) Immunobiology & Transplant Science Center, Department of Surgery, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA. (6) Immunobiology & Transplant Science Center, Department of Surgery, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA. (7) Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, USA. (8) Immunobiology & Transplant Science Center, Department of Surgery, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA. (9) Immunobiology & Transplant Science Center, Department of Surgery, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA. (10) Immunobiology & Transplant Science Center, Department of Surgery, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA. (11) Systems Medicine and Bioengineering Department, Houston Methodist Neal Cancer Center, Houston, TX, USA. (12) Systems Medicine and Bioengineering Department, Houston Methodist Neal Cancer Center, Houston, TX, USA. Department of Radiology, Houston Methodist Hospital, Weill Cornell Medicine, Houston, TX, USA. (13) Department of Surgery, J. C. Walter Jr. Transplant Center, Houston Methodist Hospital, Houston, TX, USA. Department of Surgery, Weill Cornell Medicine, Cornell University, New York, NY, USA. (14) Department of Surgery, J. C. Walter Jr. Transplant Center, Houston Methodist Hospital, Houston, TX, USA. Department of Surgery, Weill Cornell Medicine, Cornell University, New York, NY, USA. (15) Immunobiology & Transplant Science Center, Department of Surgery, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA. Department of Surgery, Weill Cornell Medicine, Cornell University, New York, NY, USA. (16) Immunobiology & Transplant Science Center, Department of Surgery, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA. wchen@houstonmethodist.org. Department of Surgery, Weill Cornell Medicine, Cornell University, New York, NY, USA. wchen@houstonmethodist.org.
