Ending Organ Transplant Rejection

In the absence of antigen, naïve CD4+ T cells remain naïve and there is no T-cell response. Upon encountering the alloantigen, the CD4+ T cells are activated and differentiate into effector helper T cells. Not all T cells recognize transplant antigens. The dynamics of the antigen-specific T-cell response have been extensively studied. However, the mechanisms that drive T cell effector programs and how the effector T cell sub-population is sustained for long periods are not known. “There are a few gaps in our understanding,” said Chen. “Although short-term graft survival has significantly improved in the last two decades, long-term graft survival is severely limited, and graft rejection is a major reason for the long–term loss of grafts.” Effector T cells are short-lived. Yet, the immune response is sustained in the patient receiving the transplant. As a transplant immunologist, Chen wondered how the alloreactive T cells always persist in the recipient. Chen and his team performed single-cell RNA sequencing in alloantigen-specific CD4+ T cells post-heart transplantation from the spleen and heart in a murine model to detect transcriptomic changes. Two major alloreactive CD4+ T cell populations were found: stem-like effector precursor T (T_EP) cells and effector cells. The T_EP cells had the capacity for self-renewal and the potential to differentiate into effector cells whereas the effector cells lacked proliferative ability, became prone to apoptosis, and did not persist.

“The big contribution of our study is identifying the stem-like T cells as the “troublemakers” responsible for transplant rejection. We call these T cells ‘stem-like’ because they behave like stem cells. Of course, they are not stem cells,” Chen explained. Some key molecules involved in determining this intrinsic stem-like program are transcription factors T-cell factor-1 (TCF-1) and interferon regulatory factor 4 (IRF-4), and the metabolic enzyme lactate dehydrogenase A (LDHA). Using knockdown models, Chen demonstrated that TCF-1 is a crucial determinant of the self-renewal capacity of the T_EP cells. On the other hand, IRF4 and LDHA are important for effector differentiation. Future directions would include investigating techniques and consequences of deleting the stem-like CD4+ T cells to test the hypothesis that deleting these stem-like T cells will lead to cessation of graft rejection. “If we can find a way to eliminate the stem-like T cells specific for the transplanted organ, there would be no organ rejection. Currently, transplant patients have to take immunosuppressive drugs every day. There will be no need for immunosuppressive drugs daily if we can find a way to delete the stem-like T cells activated by alloantigens. This system should work in all T-cell responses including ulcerative colitis and autoimmune diseases as well,” Chen noted.