ROCK2 signaling is required for development and function of T follicular helper cells (HUM3P.247)

Abstract

Abstract PD1+CXCR5+ T follicular helper (Tfh) cells are essential for generating high-affinity antibodies and B cell memory. But aberrant Tfh activity can drive autoimmune disease such as systemic lupus erythematosus (SLE) which is characterized by high levels of auto-antibodies and increased frequencies of IL-21+ T cells. Rho-associated kinase (ROCK) 2 was recently shown to be critical in regulating IL-21 secretion in both mice and humans. Here, we show that the PD1+CXCR5+ subset is a major source of IL-21 in human CD4+ T cells stimulated in vitro. By using KD025, a Kadmon orally available, selective ROCK2 inhibitor, we attenuated the development of PD1+CXCR5+ T cells by over 60% and the perpetuation of existing Tfh cells in a dose dependent manner. Targeting of ROCK2 concurrently regulates STAT3/STAT5 phosphorylation and transcription activity followed by a reduction of Bcl6 and up-regulation of Blimp1 protein levels in human T cells. Oral administration of KD025 reduced the percent of both Tfh and plasma B cells in spleens by more than 2 fold as well as germinal center size in the Mrl/lpr murine model of SLE. KD025 treated animals had a substantial improvement in both histological and clinical scores complimented by a reduction in pSTAT3 and BCL6 expression in addition to an increase in STAT5 phosphorylation. This data suggests that ROCK2 controls the function of Tfh cells and underscores the therapeutic potential of targeted ROCK2 inhibition in the clinic.