Human Treg Can Suppress Th17 Inflammatory Cytokine Secretion Independent of IL-2 Deprivation

Human Th17 cells are an inflammatory subset of CD4⁺ (CD4) T helper cells implicated in host of debilitating diseases and disorders such as multiple Sclerosis, rheumatoid arthritis, and psoriasis, as well as inhibitor formation in Hemophilia A. Although it is well established that regulatory CD4T cells (Tregs) can suppress other T helper (Th) effector cells (e.g. Th1, Th2, etc), their ability to suppress human Th17 cells is unresolved. This is attributed to several factors including plasticity between Treg and Th17 cells, the observation that Th17 cells express less IL-2 (and by extension are less dependent on IL-2) than other Th effector cells and consequently are less susceptible to Treg suppression via IL-2 deprivation. Using autologous naïve Tregs and effector memory CCR6⁺ CD4 T cells differentiated to Th17 cells from healthy human donor peripheral blood mononuclear cells, we performed a kinetic analysis of the IL-2 sensitivity via phosphorylated STAT5 expression. We show that Treg and Th17 cells have similar rates of pSTAT5 expression in vitro. We also show that both cell types have similar expression levels of the high affinity IL-2a receptor, CD25, following activation. Despite this, naïve Tregs successfully abrogated the secretion of IL17A by Th17 cells following 12hr co-culture. Furthermore, this abrogation is dependent on the strength of Treg activation and does not involve cytotoxic mechanisms, as viability of the Th17 cells remain high. These results suggest that human Tregs can suppress inflammatory IL-17A secretion from effector memory Th17 cells via mechanisms independent of IL-2 deprivation but dependent on strength of activation through Treg T-cell receptor. (Supported by NIH grant R01 HL126727)