Abdel-Hakeem, M. S., S. Manne, J. - C. Beltra, E. Stelekati, Z. Chen, K. Nzingha, M. - A. Ali, J. L. Johnson, J. R. Giles, D. Mathew, et al., "Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation.", Nature immunology, vol. 22, issue 8, pp. 1008-1019, 2021. Abstract

Exhausted CD8 T cells (T) are a distinct state of T cell differentiation associated with failure to clear chronic viruses and cancer. Immunotherapies such as PD-1 blockade can reinvigorate T cells, but reinvigoration is not durable. A major unanswered question is whether T cells differentiate into functional durable memory T cells (T) upon antigen clearance. Here, using a mouse model, we found that upon eliminating chronic antigenic stimulation, T cells partially (re)acquire phenotypic and transcriptional features of T cells. These 'recovering' T cells originated from the T cell factor (TCF-1) T progenitor subset. Nevertheless, the recall capacity of these recovering T cells remained compromised as compared to T cells. Chromatin-accessibility profiling revealed a failure to recover core memory epigenetic circuits and maintenance of a largely exhausted open chromatin landscape. Thus, despite some phenotypic and transcriptional recovery upon antigen clearance, exhaustion leaves durable epigenetic scars constraining future immune responses. These results support epigenetic remodeling interventions for T cell-targeted immunotherapies.

Kotzin, J. J., F. Iseka, J. Wright, M. G. Basavappa, M. L. Clark, M. - A. Ali, M. S. Abdel-Hakeem, T. F. Robertson, W. K. Mowel, L. Joannas, et al., "The long noncoding RNA regulates CD8 T cells in response to viral infection.", Proceedings of the National Academy of Sciences of the United States of America, vol. 116, issue 24, pp. 11916-11925, 2019. Abstract

The transcriptional programs that regulate CD8 T-cell differentiation and function in the context of viral infections or tumor immune surveillance have been extensively studied; yet how long noncoding RNAs (lncRNAs) and the loci that transcribe them contribute to the regulation of CD8 T cells during viral infections remains largely unexplored. Here, we report that transcription of the lncRNA is specifically induced by T-cell receptor (TCR) and type I IFN stimulation during the early stages of acute and chronic lymphocytic choriomeningitis virus (LCMV) infection. In response to type I IFN, the RNA and its locus control CD8 T cell expansion, survival, and effector function by regulating the expression of the proapoptotic factor, , and by modulating the strength of the PI3K-AKT signaling pathway. Thus, our results demonstrate that inflammatory cue-responsive lncRNA loci represent fundamental mechanisms by which CD8 T cells are regulated in response to pathogens and potentially cancer.

McLane, L. M., M. S. Abdel-Hakeem, and J. E. Wherry, "CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer.", Annual review of immunology, vol. 37, pp. 457-495, 2019. Abstract

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, metabolic dysregulation, poor memory recall and homeostatic self-renewal, and distinct transcriptional and epigenetic programs. The ability to reinvigorate Tex cells through inhibitory receptor blockade, such as αPD-1, highlights the therapeutic potential of targeting this population. Emerging insights into the mechanisms of exhaustion are informing immunotherapies for cancer and chronic infections. However, like other immune cells, Tex cells are heterogeneous and include progenitor and terminal subsets with unique characteristics and responses to checkpoint blockade. Here, we review our current understanding of Tex cell biology, including the developmental paths, transcriptional and epigenetic features, and cell intrinsic and extrinsic factors contributing to exhaustion and how this knowledge may inform therapeutic targeting of Tex cells in chronic infections, autoimmunity, and cancer.

Abdel-Hakeem, M. S., "Viruses Teaching Immunology: Role of LCMV Model and Human Viral Infections in Immunological Discoveries.", Viruses, vol. 11, issue 2, 2019. Abstract

Virology has played an essential role in deciphering many immunological phenomena, thus shaping our current understanding of the immune system. Animal models of viral infection and human viral infections were both important tools for immunological discoveries. This review discusses two immunological breakthroughs originally identified with the help of the lymphocytic choriomeningitis virus (LCMV) model; immunological restriction by major histocompatibility complex and immunotherapy using checkpoint blockade. In addition, we discuss related discoveries such as development of tetramers, viral escape mutation, and the phenomenon of T-cell exhaustion.

Boisvert, M., M. Abdel–Hakeem, J. Bruneau, H. Soudeyns, and N. H. Shoukry, "High avidity and functionality of virus-specific CD8 T cells associated with protection during HCV reinfection ", IMMUNOLOGY 2015, ew Orleans, LA, USA, American Association of Immunologists (AAI), 2015.
Abdel–Hakeem, M. S., O. Khan, E. Stelekati, M. - A. Ali, and E. J. Wherry, "Reprogramming of exhausted T cells following elimination of chronic antigen exposure.", IMMUNOLOGY 2017, Washington, D.C., American Association of Immunologists (AAI), pp. 198.5., 2017.
Sarhan, M. A., M. S. Abdel–Hakeem, A. L. Mason, L. D. Tyrrell, and M. Houghton, "Glycogen synthase kinase 3β inhibitors prevent hepatitis C virus release/assembly through perturbation of lipid metabolism. ", Scientific Reports, vol. 7, pp. 2495, 2017.
Abdel–Hakeem, M. S., M. Boisvert, J. Bruneau, H. Soudeyns, and N. H. Shoukry, "Selective Expansion of High Functional Avidity Memory CD8 T cell Clonotypes during Hepatitis C Virus Reinfection and Clearance", PLOS Pathogens, vol. 13, issue 2, pp. e1006191, 2017.
Abdel-Hakeem, M. S., N. Bédard, G. Badr, M. Ostrowski, J. Bruneau, R. P. Sékaly, B. Willems, J. E. Heathcote, and N. H. Shoukry, Early but not late interferon alpha therapy against hepatitis C rescues polyfunctional CD4+ and CD8+ memory T cells, , Montréal, Québec, CANADA, 2008. conf._proc._my_2008_-_cytokine.pdf
Badr, G., N. Bédard, M. S. Abdel-Hakeem, L. Trautmann, B. Willems, J. - P. Villeneuve, E. K. Haddad, R. P. Sékaly, J. Bruneau, and N. H. Shoukry, "Early Interferon Therapy for Hepatitis C Virus Infection Rescues Polyfunctional, Long-Lived CD8! Memory T Cells", JOURNAL OF VIROLOGY, vol. 82, issue 20, pp. 10017–10031, 2008. AbstractWebsite

The majority of acute hepatitis C virus (HCV) infections progress to chronicity and progressive liver damage.
Alpha interferon (IFN-!) antiviral therapy achieves the highest rate of success when IFN-! is administered
early during the acute phase, but the underlying mechanisms are unknown. We used a panel of major
histocompatibility complex class I tetramers to monitor the phenotypic and functional signatures of HCVspecific
T cells during acute HCV infection with different infection outcomes and during early IFN therapy. We
demonstrate that spontaneous resolution correlates with the early development of polyfunctional (IFN-"- and
IL-2-producing and CD107a#) virus-specific CD8# T cells. These polyfunctional T cells are distinguished by
the expression of CD127 and Bcl-2 and represent a transitional memory T-cell subset that exhibits the
phenotypic and functional signatures of both central and effector memory T cells. In contrast, HCV-specific
CD8# T cells in acute infections evolving to chronicity expressed low levels of CD127 and Bcl-2, exhibited
diminished proliferation and cytokine production, and eventually disappeared from the periphery. Early
therapeutic intervention with pegylated IFN-! rescued polyfunctional memory T cells expressing high levels of
CD127 and Bcl-2. These cells were detectable for up to 1 year following discontinuation of therapy. Our results
suggest that the polyfunctionality of HCV-specific T cells can be predictive of the outcome of acute HCV
infection and that early therapeutic intervention can reconstitute the pool of long-lived polyfunctional memory
T cells.