Dysfunctional effector programming in Foxp3-ΔE2 Tregs promotes enhanced CD8+ T cell responses

Abstract

Regulatory T cells (Tregs) prevent autoimmunity through suppressive functions largely programmed by the transcription factor FOXP3. Humans express two major alternatively spliced isoforms of FOXP3: a full-length version containing all coding exons (FOXP3-FL) and a version lacking Exon 2 (FOXP3-{Delta}E2). Sole FOXP3-{Delta}E2 expression causes lethal IPEX syndrome, indicating that FOXP3 Exon 2 is essential for full Treg function. Here, we used Foxp3-{Delta}E2 mice to determine how Foxp3 Exon 2 impacts the functional differentiation of Tregs at homeostasis and during inflammation. Analysis of central and effector Foxp3-{Delta}E2 Treg populations revealed dysfunctional effector Treg programming, including reduced expression of IL-2 receptor subunits, CTLA-4, and tissue-homing chemokine receptors. During influenza infection, reduced IL-2 regulation by Foxp3-{Delta}E2 Tregs and decreased Foxp3-{Delta}E2 Treg localization to the T cell zone during priming contributed to enhanced acute and memory CD8+ T cell responses. Thus, dysfunctional effector Treg programming by the Foxp3-{Delta}E2 isoform impairs suppressive function, resulting in failure to restrain CD8+ T cells and aberrant immune responses.