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

Abstract

ABSTRACTAdoptive therapy with genetically engineered T cells 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) T cells designed to recognize PS-expressing cells could eliminate SIV infected cells. Lentiviral CER constructs comprised of the extracellular domain of T-cell immunoglobulin and mucin domain containing 4 (TIM-4), the PS receptor, and engulfment signaling domains were transduced into primary rhesus macaque (RM) T cells. We measured PS binding and T-cell engulfment of RM CD4+ T cells infected with SIV expressing GFP. As chimeric antigen receptor (CAR) T cells induce PS and subsequent TIM-4 binding, we evaluated in vitro killing of CAR and CER T-cell combinations. We found that recombinant TIM-4 bound to SIV infected cells. In vitro, CER CD4+ T cells effectively killed SIV infected cells, which was dependent on TIM-4 binding to PS. Enhanced killing of SIV infected CD4+ T cells by CER and CAR T-cell combinations was observed. This installation of innate immune functions into T cells presents an opportunity to enhance elimination of SIV infected cells and offers potential to augment functional cure of SIV/HIV infection.