Novel engineered chimeric engulfment receptors trigger T cell effector functions against SIV-infected CD4+ T cells

Abstract

Adoptive therapy with genetically engineered Tcells offers potential for infectious disease treatment in immunocompromised persons. HIV/simian immunodeficiency virus (SIV)-infected cells express phosphatidylserine (PS) early post infection. We tested whether chimeric engulfment receptor (CER) Tcells designed to recognize PS-expressing cells could eliminate SIV-infected cells. Lentiviral CER constructs composed of the extracellular domain of Tcell immunoglobulin and mucin domain containing 4 (TIM-4), the PS receptor, and engulfment signaling domains were transduced into primary rhesus macaque (RM) Tcells. We measured PS binding and Tcell engulfment of RM CD4+ Tcells infected with SIV expressing GFP and invitro, TIM-4 CER CD4+ Tcells effectively killed SIV-infected cells, which was dependent on TIM-4 binding to PS. Enhanced killing of SIV-infected CD4+ Tcells by CER and chimeric antigen receptor Tcell combinations was also observed. This installation of innate immune functions into Tcells presents an opportunity to enhance elimination of SIV-infected cells, and studies to evaluate their effect invivo are warranted.