In humans, IL4 and TH2 cells critically impact a wide array of diseases, a prime example of which is bronchial asthma where genetic association studies have repeatedly identified both the gene locus encoding IL4 and IL13 (5q25-31) and several mutations in the IL4 receptor alpha chain as strong disease risk factors REF. We recently identified Mina53 as a gene in mice encoding an IL4 regulatory protein that cell autonomously regulates TH2 bias, the propensity of naive CD4 cells to develop into IL4 secreting TH2 cells [1]. Mina53, first identified as a Myc-induced nuclear antigen of 53kd [2], belongs to the Jmj protein family whose hallmark JmjC domain was shown recently in multiple family members to possess histone demethylase activity [3-9]. Murine Mina53 is induced rapidly in naive T helper cells to levels that are inversely correlated with those of IL4, being high in low-TH2 biased strains and low in high-TH2 biased strains, suggesting an IL4/TH2 inhibitory role. Consistent with this, EMSA, chromatin immunoprecipitation (ChIP), transient reporter and transgenic animal assays demonstrate that Mina53 specifically binds to and represses transcription from the IL4 gene. Together, these data support the central hypothesis of this proposal that in human T cells, MINA53 represses IL4 expression, thereby critically influencing TH2 development and TH2-dependent disease. We will test this hypothesis by determining: (1) the role of MINA53 in regulating IL4 and TH2 bias in human T helper cells;and (2) whether variation in the MINA53 locus associates with the TH2-dependent disease bronchial asthma. The long-term objective of this proposal is to understand the molecular and genetic basis for IL4/TH2- dependent disease and to identify novel targets for diagnostic and therapeutic intervention. PUBLIC HEALTH RELEVANCE: The global significance of this proposal arises from the critical role of TH2 bias in immune responses elicited by tolerogens, pathogens and allergens. Deeper mechanistic understanding of TH2 bias and its role in bronchial asthma may provide new targets for diagnostic and therapeutic interventions for asthma as well as for other TH2-dependent disease of autoimmune, infectious and allergic etiology affecting the lives of millions of people.