T follicular helper and memory cell responses and the mTOR pathway in murine heart transplantation

Abstract

BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitors are valuable immunosuppressants in clinical transplantation, but mTOR regulation of allogeneic T cell responses is not fully understood. Here, we investigated the effects of T cell-specific mTOR deletion on allogeneic T cell responses and heart transplant survival. METHODS:Wild type C57BL/6, Mtor fl/fl Cd4-Cre, Stat3 fl/fl Cd4-Cre, and Mtor fl/fl Stat3 fl/fl Cd4-Cre mice were transplanted with BALB/c heart allografts, with or without BALB/c skinsensitization. Graft survival and histology, as well as T cell frequencies and phenotypes, were evaluated after transplantation. RESULTS:In the absence of donor skin-sensitization, long-term heart allograft survival was achieved in Mtor fl/fl Cd4-Cre recipients, which was associated with significantly decreased frequencies of CD62L − CD44 + effector T cells and BCL-6 + CXCR5 + T follicular helper (Tfh) cells in the periphery. Long-term heart allograft survival was also achieved in donor skin-sensitized Mtor fl/fl Stat3 fl/fl Cd4-Cre mice, whereas heart allograft survival was prolonged in donor skinsensitized Mtor fl/fl Cd4-Cre and Stat3 fl/fl Cd4-Cre mice.CONCLUSIONS: mTOR is required for Tfh cell response in murine heart transplantation. T cellspecific deletion of both mTOR and Stat3 abrogates memory response to heart transplants. These findings help us to better understand the molecular mechanisms underlying T cell immunity to transplanted organs.

Investigation of hub genes and immune status in heart transplant rejection using endomyocardial biopsies

“…(b) Activated CD4 + /CD8 + T cell responses play a critical role in heart graft rejection 19,42,43 . (c) Activated pro‐inflammatory follicular helper T cells help to generate donor‐specific antibody (DSA) responses after organ transplantation, which is an attractive target for improving the effects of immunosuppressive drugs 44,45 . (d) Treg therapy is a novel tool for delaying graft rejection following solid organ transplantation 46 .…”

Optimal Immunosuppression Strategy in the Sensitized Kidney Transplant Recipient

“…In mice sensitized by prior skin graft, preoperative rapamycin increased the expression of regulatory T cells, but did not prolong the survival of mice after cardiac allotransplantation [78]. In donor skinsensitized mice, those with mTOR deletion in T cells had longer mean survival time (MST 19.5 days) versus wild-type recipients (MST 5.4 days) [75]. Mice sensitized by skin transplant and treated with rapamycin induction therapy were found to have altered frequencies of splenic and intragraft neutrophils, macrophages, and natural killer (NK) cells [79].…”

“…The mammalian target of rapamycin (mTOR) controls the T cell response (activation and proliferation) and is a valuable immunosuppressant in clinical transplantation. mTOR inhibitors, such as rapamycin (sirolimus) and everolimus, promote the differentiation and function of various helper T cells and suppress the differentiation of memory CD8+ T cells [75]. Furthermore, unlike CNIs, mTOR inhibitors are able to prevent Ig production from B cells when cultured with primed T cells, which suggests their direct impact on B cells [67,76].…”

Harnessing the B Cell Response in Kidney Transplantation – Current State and Future Directions

“…mTOR inhibitors suppress T cell activation and differentiation via blockade of cell-cycle progression ( 111 ), inhibition of thymic maturation ( 112 ), and downregulation of chemokine signaling ( 113 , 114 ). Interestingly, rapamycin treatment results in a decrease in Tfh and effector T cells, with a relative increase in CD4 + CD25 + FOXP3 + regulatory T cells, which are implicated in attenuating memory T cell proliferation ( 32 – 34 ). However, one important advantage of mTOR inhibitors over CNIs is the direct suppression of GC formation, B cell proliferation and immunoglobulin production ( 31 , 35 , 36 ).…”