Helminthes Infection enhances GAS6 expression dampening Th17 development in patients with Multiple Sclerosis

ORTIZ WILCZYÑSKI, JUAN MANUEL; SCHATTNER, MIRTA; CARRERA SILVA, EUGENIO ANTONIO; OLEXEN, CINTHIA MARIEL; ROTHLIN CARLA V; ERRASTI, ANDREA EMILSE; CORREALE JORGE

Ciudad del Cabo

Simposio; Keystone Symposia on Molecular and Cellular Biology. Helminths: New Insights from Immunity to Global Health; 2019

Keystone Symposia

Ortiz W, Juan Manuel1; Olexen, Cinthia M1; Schattner, Mirta A1; Errasti, Andrea E2; Rothlin Carla3; Correale, Jorge4; Carrera Silva, Eugenio EA1Helminth infections are known to modulate the course of inflammatory and autoimmune diseases due to their ability to trigger regulatory mechanisms in the hosts, a phenomenon that results advantageous in such pathological context (Correale and Farez, 2007; Elliott, et al.; 2007; Fleming and Weinstock, 2012). The tyrosine kinase receptors TYRO3, AXL, and MERTK (TAM) have been described as inhibitors of the immune response in type I and type II inflammatory settings (Rothlin et al., 2007; CarreraSilva et al., 2013; Chan et al., 2016). Here, we test if helminth infections engage the TAM axis in patients with Multiple Sclerosis and influence the adaptive immune response. The TAM receptor agonist GAS6 but not PROS1 was up-regulated in circulating CD4+ T and CD11b+ cells from patients with Multiple Sclerosis that were concomitantly infected with helminthes (HIMS) compared to healthy donors (Control) or uninfected Multiple Sclerosis (MS) patients. Interestingly, when T cells were simulated with α-CD3/α-CD28 for 7 to 10 days in vitro, HIMS samples showed lower percentage of Th17 cells compared to samples from non-infected MS individuals or healthy donors. Given that both GAS6 and PROS1 need to bind phosphatidylserine (PS) in a Ca++ dependent manner to effectively activate TAM receptors, we blocked exposed PS by using Annexin V during T cell culture. The reduction of PS availability in activated T cells induced an increased percentage of IL-17 expressing cells together with higher levels of homing cell adhesion molecule CD44, but a decreased proliferation rate and CD25 expression. Similarly, blocking GAS6 with a monoclonal antibody induced an expansion of Th17 subset. Our results suggest that GAS6 is differentially induced during type 2 immunity and contribute to dampen Th17 development. This research was supported by CONICET and the ANPCyT, Argentina