Defects in CD8⁺ T cell suppression by Foxp3-ΔE2 expressing regulatory T cells

Regulatory T cells (Tregs) prevent autoimmunity through suppressive functions largely programmed by the transcription factor FOXP3. Healthy humans express approximately equivalent levels of two major alternatively spliced isoforms of FOXP3: a full-length version containing all coding exons (FOXP3-FL) and a version lacking exon 2 (FOXP3-ΔE2). However, sole FOXP3-ΔE2 expression causes lethal IPEX syndrome, and the FOXP3-ΔE2 isoform is elevated in several autoimmune diseases. These observations strongly suggest defects in suppression by FOXP3-ΔE2 Tregs which we investigated here using Foxp3-ΔE2 mice. In an influenza virus infection model, Foxp3-ΔE2 mice had an increased magnitude of the CD8⁺ T cell response during acute and memory formation phases of infection. Transcriptomic and chromatin accessibility analyses of homeostatic Foxp3-ΔE2 Tregs revealed impaired Treg programming, including reduced expression of inhibitory molecules such as Il2ra and chemokine receptors. Decreased cell surface CD25 expression on Foxp3-ΔE2 Tregs was associated with reduced IL-2 responsiveness in Foxp3-ΔE2 Tregs and, reciprocally, increased IL-2 responsiveness in CD8⁺ T cells from Foxp3-ΔE2 mice. Additionally, altered chemokine receptor expression resulted in diminished localization of Foxp3-ΔE2 Tregs to the T cell zone of the inflamed lymph node. Thus, Treg programming by the Foxp3-ΔE2 isoform impairs suppressive function, resulting in failure to restrain CD8⁺ T cells and aberrant immune responses.