There is currently no literature on the roles of histone acetyltransferases (HATs) in allograft biology, despite the central roles that these enzymes are thought to play in all cells, including lymphocytes. Given that various members of the several families of HATs are expressed in T cells, we hypothesized that they could not all be redundant, and that discrete signaling pathways and epigenetic events might be revealed upon analysis of the specific functions of individual HAT proteins. We have now generated the first data showing how a prototypical HAT from the GNAT family, GCN5 (general control nonrepressed-protein 5, KAT2A), that is evolutionarily conserved from yeast to humans, contributes to host alloresponses. GCN5 is typically found as a subunit of multiprotein complexes such as SAGA, ATAC and STAGA. We conditionally deleted GCN5 in developing thymocytes by crossing floxed GCN5 and CD4-Cre mice. GCN5 deletion had no effect on the overall development of CD4, CD8 or Foxp3+ Treg cells. Likewise, the proportions of these cells in peripheral lymph nodes and spleen were comparable to that found in wild-type (WT) controls, and conditionally deleted mice developed normally. They also displayed essentially normal Treg function. However, upon activation in vitro, GCN5-/- conventional CD4 and CD8 cells showed decreased activation, proliferation and cytokine production. In particular, IL-2 production was impaired, in conjunction with decreased acetylation of NFkB/p65 and decreased histone acetylation. Consistent with the impairment of T cell responses in vitro, corresponding C57BL/6 mice lacking GCN5 in T cells showed prolonged allograft survival when engrafted with BALB/c hearts and treated with a subtherapeutic dose of rapamycin (0.1 mg/kg/day) for up to 14 days. WT mice receiving the protocol rejected their cardiac allografts by 8-10 days, whereas allografts in GCN5-/- mice survived for a mean of 33 days (p<0.01). These data are consistent with a key role for GCN5 in promoting chromatin remodeling and recruitment of acetylated p65 to the IL-2 locus in activating T cells. Hence, GCN5 may be an important new target for epigenetic therapy in allograft recipients.
To cite this abstract in AMA style:Bao C, Liu Y, Wang L, Han R, Dent S, Hancock W. Epigenetic Mechanisms Underlying Allograft Rejection: Role of the Histone Acetyltransferase, GCN-5 in T Cell Activation, Proliferation and Cytokine Production [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/epigenetic-mechanisms-underlying-allograft-rejection-role-of-the-histone-acetyltransferase-gcn-5-in-t-cell-activation-proliferation-and-cytokine-production/. Accessed October 24, 2020.
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