Modulation of T cell receptor and interleukin-2 receptor signaling in human primary CD4+ T cells (179.7)

Abstract

Abstract Type 1 Diabetes (T1D) results from the aberrant autoimmune targeting and destruction of insulin-producing β-cells, and dysregulation of T cell activation is central to this break in tolerance. Regulatory T cells (Tregs) are fundamental to maintaining immune homeostasis and functional defects of this T cell subset can potentiate autoimmunity. Therefore, Tregs represent an attractive target for clinical intervention of T1D. Genetic variants of PTPN2 and PTPN22 have been linked to several autoimmune diseases, including T1D, by genome wide association studies. These genes encode for phosphates that dampen IL-2R and TCR signaling, respectively. In this study, we have utilized lentiviral vectors for dual overexpression and knockdown of these genes in primary human CD4+ T cells. We hypothesize that the suppressive function and phenotypic stability of human Tregs is enhanced by increased IL-2R and TCR signaling and deficient following downregulation of IL-2R and TCR signaling. Pathway-modified human effector T cells (Teff) will display altered lineage skewing and may be resistant to AICD and suppression when IL-2R and TCR signaling are increased. Further, simultaneous modulation of these pathways will synergistically affect T cell function. These data will provide insights into how direct modulation of these autoimmune signature pathways controls adaptive Treg and Teff activity, and further, have important implications for adoptive Treg therapy for the treatment of autoimmunity.