Alternate function of Foxp3 in human CD4+ T cells (179.2)

Abstract

Abstract Foxp3 is the master regulator of T-reg phenotype and function. Unlike murine T cells, human T cells express two versions of Foxp3 of which the smaller form is missing exon 2 (Δ2). Previously we showed that Foxp3Δ2 fails to up-regulate the Pim 2 kinase and others have reported that members of the ROR family bind to exon 2 of Foxp3. Nonetheless, it is not clear if these isoforms differentially affect regulatory and nonregulatory T cell function. This study demonstrate that transduction of Foxp3 and Foxp3Δ2 into primary human CD4+CD45RA+CD25- naïve T cells induced suppressive activity that was identical to natural T-regs. However, in CD4+CD45RA-CD25- memory T cells, the full-length Foxp3 construct was unable to introduce a suppressive phenotype, whereas Foxp3Δ2 retained its ability to promote suppressive activity. Furthermore, memory cells transduced with Foxp3 abrogated the suppressive functions of naïve cells transduced with Foxp3 but not with Foxp3Δ2.Cytokine profiling indicated a 3 fold increase in the IL-2+IFN-γ+ cells within the memory cells transduced with Foxp3. Altogether these observations reveal an isoform dependent alternate function of Foxp3 in the CD4+ memory T cell compartment. These studies support the use of naïve T cells for strategies that transduce effector T cells with Foxp3 expressing vectors as a means to rapidly generate T-regs for use in adoptive T cell therapy against autoimmune diseases.