LAUSR

&NA; PBX1‐d is novel splice isoform of pre‐B‐cell leukemia homeobox 1 (PBX1) that lacks its DNA‐binding and Hox‐binding domains, and functions as a dominant negative. We have shown that PBX1‐d expression in CD4+ T cells is associated with systemic lupus erythematosus (SLE) in a mouse model as well as in human subjects. More specifically, PBX1‐d expression leads to the production of autoreactive activated CD4+ T cells, a reduced frequency and function of Foxp3+ regulatory T (Treg) cells and an expansion of follicular helper T (Tfh) cells. Very little is known about the function of PBX1 in T cells, except that it directly regulates the expression of miRNAs associated with Treg and Tfh homeostasis. In the present study, we show that PBX1 directly regulated the expression of CD44, a marker of T cell activation. Two PBX1 binding sites in the promoter directly regulated CD44 expression, with PBX1‐d driving a higher expression than the normal isoform PBX1‐b. In addition, mutations in each of the two binding sites had different effects of PBX1‐b and PBX1‐d. Finally, we showed that an enhanced recruitment of co‐factor MEIS by PBX1‐d over PBX1‐b, while there was no difference for co‐factor PREP1 recruitment. Therefore, this study demonstrates that the lupus‐associated PBX1‐d isoform directly transactivates CD44, a marker of CD44 activation and memory, and that it has different DNA binding and co‐factor recruitment relative to the normal isoform. Taken together, these results confirm that PBX1 directly regulates genes related to T cell activation and shows that the lupus‐associated isoform PBX1‐d has unique molecular functions. HighlightsPBX1‐d is novel splice isoform of PBX1 that is expressed in lupus CD4+ T cells.PBX1 binds to the CD44 promoter and directly regulates its expression.PBX1‐d enhances CD44 expression relative to PBX1‐b, the normal PBX1 isoform.PBX1‐d and PBX1‐b have different DNA binding and co‐factor recruitment requirement.