Exhausted T cells (TEX) are a hallmark of chronic viral infection and cancer, induced by persistent antigenic stimulation that results in progressive loss of function and failure to clear tumors and virus-infected cells. T cell exhaustion is an independent differentiation path, reflected by unique cellular, transcriptional, metabolic, and epigenetic TEX profiles distinct from effector/memory T cells (TEFF/TMEM) generated in the context of acute infection.
My research work focuses on dissecting the correlates, factors, and mechanisms associated with differentiation of T cells during chronic viral infections, generally termed “exhausted” T cells (TEX). We studied TEX differentiation upon spontaneous and treatment-induced viral clearance at different phases of chronic infection, as well as upon re-encountering their cognate antigen during reinfection episodes post-clearance and post-cure of primary infection episodes. For these studies, we used both mouse models which enable mechanistic insights, and human samples that confirm the translational relevance of basic immunology findings. These studies aimed at investigating the aspects of the T cell “exhaustion” program that could be reversed upon eliminating persistent antigenic stimulation, and the correlates of protective capacity of T cells that encountered chronic viruses. Results from these studies shed light on important aspects of recovery from different aspects of T cell exhaustion on the cellular, transcriptional, and epigenetic levels, as well as provided first insights on cellular correlates of potentially protective T cell responses. Follow-up studies are pivotal to gain deeper insights into the biology of T cell exhaustion and enhance our potential to harness the immunotherapeutic and protective capacities of TEX against chronic viral infection and cancer.
Discrepancy between the transcriptional and proteomic profiles of cells was underscored by many studies from different fields of biology. However, no studies to date dissected the proteomic landscape of TEX or TEFF/TMEM directly ex-vivo. We performed protein abundance profiling of TEX compared to TEFF/TMEM post-infection with lymphocytic choriomeningitis virus (LCMV) Clone13 and Armstrong, that cause chronic and acute infections, respectively. Our preliminary proteomic analyses showed significantly different abundance of more than 200 proteins in TEX compared to TMEM, including proteins that were previously underappreciated by transcriptional analysis,
Dr. Abdel Hakeem earned his PhD and his MSc in microbiology and immunology from Université de Montréal, in Montreal, Canada. He completed his postdoctoral training at University of Pennsylvania in Philadelphia, Pennsylvania.
Mohamed Abdel Hakeem, PhD, MSc, Bpharm, is assistant professor in the Department of Pathology and Laboratory Medicine at Emory University School of Medicine.
Dr. Abdel Hakeem is a member of the Cancer Immunology Research Program at Winship Cancer Institute