The Regulation Of CD4~+ T Lymphocytes By Transcription Factor Zfp281 And The Underlying Mechanism

T lymphocytes origins from early T lineage precursors. According to the surface expression of CD4 and CD8, T cell development in thymus were devided into four stages including double negative, double positive, CD4+and CD8+single positive. Single positive cells finally export to peripheral lymphoid organs for immune response. Series of singnaling pathways and transcription factors were involved in T cell development and activation. For instance, GATA-3 determined the development of CD4+T cells, while RUNX3 for CD8+T cells. T cell activation was influenced by the level of NFAT phosphorylation and de-phosphorylation. The activation of peripheral T cell is required for two signals, one from antigen, another from costimulator. Furthermore, there are negative feedback mechanisms for T cell activation such as coinhitor CTLA-4. Costimulator CD28 promoted T cell activation, and CD28 deficiency mice showed decreased proliferation of T cells. Coinhibitor CTLA4 inhibit T cell activation, and CTLA-4 knockout mice died three weeks after birth due to excessive proliferation of T cells. CTLA-4 plays an important role in T cell activation, but there is few report about the transcritional regulation of CTLA-4.The trancription factor Zfp281 belongs to a novel class of transcription factor that contains a characteristic array of four kruppel type zinc fingers and are phylogenetically conserved in mammals. Zfp281 is more highly expressed in the early emybro development. It is the focus of current researches that Zfp281 regulated pluripotent stem cells and embryo development. It has shown that Zfp281 sustained the multipotency of embryo stem cells by interacting with Oct4, Sox2 and Nanog. In addition, Zfp281 mRNA is expressed ubiquitously at low levels, with elevated expresseion levels in pancreas, kidney, liver and peripheral lymphocytes. However, the function and role of zfp281 in adult cells has not been described. Given that Zfp281 deletion result in early embryonic lethality, we constructed Zfp281 conditional knockout mice with Cre-Loxp system. Then we used CD4 Cre mediated approach to evaluate the cell autonomous role for zfp281 in murine T lymphocytes. T cell development, peripheral cellularity and cell surface phenotype are normal in the absence of Zfp281. T cell proliferation was also normal in Zfp281-decificiency mice. However, Zfp281 conditional knockout mice showed impaired T cell activation and decreased cytokine produciton which was further confirmed by Listeria Monocytogenes infection. RNA-seq suggested that Zfp281 function as a repressor. We indentified CTLA-4 as one of Zfp281 targets by ChIP. Taken together, our data demonstrate that Zfp281 sustain T cell activation via directly targeting coinhibitor CTLA-4.