HOXA9-PBX1 axis orchestrates divergent Th2 cytokine expression

Evolutionarily conserved HOXA9 is a well-known player of hematopoiesis and leukemogenesis. However, the involvement of this transcription factor in CD4+ T cell development is largely unexplored. Th2 cells play a critical role in the pathogenesis of numerous autoimmune disorders. The development of this heterogenic subpopulation of cells is orchestrated by a consortium of factors including GATA3 and PU.1, among others. Here, we recognized the molecular regulation bestowed by HOXA9 in Th2 cell development. We found that overexpression of HOXA9 in Th2 cell leads to increased secretion of IL-10 while suppressing IL-4 and IL-13. Through promoter activity analysis, we determined the crucial role played by the structural domains of HOXA9 on Th2-specific cytokines. These findings further indicated the presence of other cofactors that contribute to the functional activity of HOXA9. Our findings demonstrated that HOXA9 can engage in physical interactions with PU.1 and PBX1, but not with GATA3, and exhibits direct binding to PU.1-specific chromosomal loci within Th2 cells. PBX1 overexpression stimulates the secretion of IL-4, IL-13, and IL-10. In contrast, the combined overexpression of HOXA9 and PBX1 suppresses IL-4 and IL-13 secretion but boosts IL-10 production. Taken together, the data suggest that PBX1 acts specifically as a coregulator for HOXA9 in the context of Th2 cell function. The contribution of HOXA9 and PBX1 is significantly more pronounced in the proximal promoter region of the Il10 gene. This study has significantly advanced our understanding of Th2 cell differentiation and cytokine production, regulated by HOXA9-PBX1 axis through interactions with other key transcription factors.