*Purpose: Ikaros is a transcriptional repressor encoded by the Ikzf1 gene that was recently identified as the pharmacologic target of thalidomide analogs in successful therapy for myeloma. We have previously shown that Ikaros controls conventional T cell (Tconv) differentiation and tolerance. Tconv regulate Ikaros expression in response to antigenic and inflammatory cues, and Tconv with defective Ikaros activity fail to repress cytokine production in response to costimulatory blockade and other tolerance-inducing signals. Unlike Tconv, regulatory T cells (Treg) express multiple members of the Ikaros family (e.g., Ikaros, Helios, Eos), but the role of each of these proteins in Treg function is unclear.

*Methods: To determine whether Ikaros is specifically required for Treg function, we generated conditional Ikzf1-fl/fl-Foxp3-YFP-Cre mice in which Ikzf1 is specifically deleted in the Treg lineage.

*Results: Like Ikaros-deficient Tconv, Ikaros-deficient Treg showed failed silencing of pro-inflammatory cytokine gene expression. Mice with Treg-specific loss of Ikaros function showed spontaneous accumulation of activated Tconv in vivo, suggesting that Ikaros expression by Treg is required for maintenance of tolerance to self and/or innocuous antigens. We found that Ikaros expression in the Treg lineage is also required for acquired immune tolerance, because while CD28 and CD40L blockade induced long-term cardiac allograft tolerance in Ikaros-sufficient control mice, Ikzf1-fl/fl-Foxp3-YFP-Cre recipients rejected their allografts in the face of costimulatory blockade.

*Conclusions: These studies establish a non-redundant, Treg-intrinsic role for Ikaros in Treg function, and implicate Ikaros as a potential new therapeutic target for modulating transplantation tolerance.

« Back to 2019 American Transplant Congress