Deprogramming Transplant Rejection

Transplanted tissues and organs are recognized as “other” by our immune systems, thus, triggering an immune response that results in physiological rejection of the tissue. To prevent this, physicians must modulate immunity, so the immune response is not clinically significant, and the foreign object is tolerated. Measures can be taken before and after transplant to reduce the risk of rejection. Before transplantation, testing ensures that donors and recipients have compatible blood types and genetic profiles that are closely matched, with a preference for the better matched donors. After transplantation, anti-rejection medications are prescribed, and blood work is monitored frequently to ensure transplant success and prevent unwanted side effects.

To gain deeper insight into the role of CD4⁺ T cells in transplant rejection, Chen’s study utilized single-cell RNA sequencing to analyze the CD4⁺ T cell response in transplantation scenarios. Published recently in Nature Immunology, the results indicate the presence of stem-like CD4⁺ T cells in transplant recipients, as well as the stem-like program directing the CD4⁺ T cell response in models of transplantation. More specifically, they found stem-like CD4⁺ T cells that recognize transplant antigens and can differentiate into effector cells that attack transplanted organs. Their data indicate that naïve alloantigen-specific CD4⁺ T cells develop first into TCF1^hi effector precursor T (T_EP) cells and then into TCF1–CXCR6+ effector cells. However, the effector cells lose their ability to proliferate and fail to reject allografts upon adoptive transfer into new recipients. Conversely, the TCF1^hi CD4⁺ TEP cells can self-renew and differentiate into effector cells, thereby representing the stem-like CD4⁺ T cells in transplantation scenarios. Crucially, the rejection of allografts is dependent on continuous replenishment of TCF1–CXCR6+ effectors from TCF1^hi CD4⁺ T_EP cells. Moreover, the sustainability of the CD4⁺ T_EP cell population is largely dependent on TCF1, while the differentiation into effector cells requires other factors, including the transcription factor IRF4 and the glycolytic enzyme LDHA. In fact, IRF4 or LDHA deletion in T cells resulted in transplant acceptance. These results provide robust evidence for a stem-like program that controls the self-renewal and effector differentiation abilities of CD4⁺ T_EP cells. Because the stem-like CD4⁺ T cells continually replenish the effector cell pool, they might be the more effective therapeutic target for preventing transplant rejection and in other T cell-related immunotherapies. “This revelation about the true ‘troublemaker’ within the CD4⁺ T cell population is just the tip of the iceberg. I sincerely hope that our findings garner widespread attention, motivating both researchers and patients to recognize the significance of targeting these ‘troublemakers,’” said Chen.