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

• Published in: Molecular therapy. Methods & clinical development Vol. 28; pp. 1 - 10
• Main Authors: Corey, Daniel, Haeseleer, Francoise, Hou, Joe, Corey, Lawrence
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.03.2023; American Society of Gene & Cell Therapy; Elsevier
• Subjects: chimeric engulfment receptor (CER); HIV; Original; phosphatidylserine; SIV; TIM-4; SIV; phosphatidylserine; HIV; chimeric engulfment receptor (CER); TIM-4
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2022.11.004

Adoptive 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 composed 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 and in vitro, TIM-4 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 chimeric antigen receptor T cell combinations was also observed. This installation of innate immune functions into T cells presents an opportunity to enhance elimination of SIV-infected cells, and studies to evaluate their effect in vivo are warranted. [Display omitted] Corey and colleagues have characterized chimeric engulfment receptor (CER) T cells aimed at targeting phosphatidylserine expressing cells, including apoptotic cells and SIV/HIV-infected cells. The CER T cells based on the TIM-4 binding protein fused to signaling domains from receptors involved in innate immune responses can eliminate SIV-infected cells.