Treg mediated immune system homeostasis requires NKAP association with HDAC3

Abstract

Abstract NKAP is a transcriptional regulator essential for conventional T cell maturation. It does not have any previously defined DNA binding domains and is thought to interact with HDAC3 to exert its functions. The deletion of NKAP at the double positive stage (DP) in T cell development using the CD4-cre NKAP conditional knockout (cKO) mouse model renders thymocytes unable to incorporate α2,8-linked sialic acids and upregulate the complement inhibitory protein CD55, leading to rapid elimination of RTEs by complement. Here, we interrogate the importance of NKAP in Tregs. To address this, we created the Foxp3-YFP-cre NKAP cKO mouse model to delete NKAP only in the Treg lineage. Loss of NKAP in Tregs results in their disappearance, culminating in systemic autoimmunity, similar to the “scurfy” phenotype of Foxp3 mutant mice. Mice with Tregs lacking NKAP have increased conventional T cell proliferation, lymphocytic infiltration into various organs, and crusty skin on tail and ears, which necessitate euthanasia by three weeks. Preliminary results indicate that the disappearance of Tregs is a result of increased complement deposition. Transgenic expression of wildtype NKAP in a cre-inducible manner in cKO mice ameliorates the lymphoproliferative disease by restoring normal Treg numbers, and the mice are healthy. Interestingly, transgenic expression of a mutant version of NKAP that has lost its ability to bind HDAC3 is unable to prevent autoimmunity. Previous studies have demonstrated that HDAC3 is important for the generation and function of Tregs. Our results indicate that NKAP’s binding with HDAC3 is important for its role in Treg mediated immune system homeostasis.