Defining the transcriptomic and epigenetic blueprint of anti-viral T cell memory and the role of novel transcription factors in memory generation

• Applicant: Muhammad Zeeshan Chaudhry, Ph.D.
• Subject Area: Immunology ; Virology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 468129197

Antiviral CD8+ T cells constitute a critical arm of immune system that fight virus infections and mediate pathogen clearance from the body. Chronic virus infections such as persistent lymphocytic choriomeningitis virus (LCMV) infection of adult mice, and hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections of humans induce chronic inflammatory conditions that ultimately exhaust the adaptive host immune system over time, in particular the CD8+ T cell. In contrast, herpesviruses such as cytomegalovirus (CMV) persist and coexist in the host in an inactive latent form and do not cause widespread immune dysregulation. Control of CMV infection, distinct from other virus infections, depends largely on the accumulation of a unique population of terminally-differentiated virus-specific effector CD8＋ T cells known as inflationary T cells, which currently are only poorly understood. Chronic virus infections constitute a major clinical challenge to humanity, and it remains unclear why different chronic infections result in diametrically opposing T cell responses in immune control strategies. Although several aspects of T cell differentiation have been described, defining key attributes of memory T cell formation and a universal transcriptional blueprint of this process has been a major challenge.CD8+ T cell responses following chronic LCMV and CMV infection in the mouse model will be studied. The transcriptional and epigenetic profile of the memory CD8+ T cells generated following virus infection will be assessed using state-of-the-art genomic technologies. The temporal dynamics of stem-cell like T cells that emerge early upon virus infection will be defined using unique reporter mouse strains available in Belz laboratory. Mouse strains that lack transcription factors (Irf4-/- and Tox-/-Tox2-/- mouse models) will be used to understand the role of these TFs in T cell responses to chronic virus infections. Moreover, a major objective of this project is to delineate a core cellular and molecular blueprint of T cells that contribute to long-term protective immunity and understand how different pathways are generated. To provide an integrated understanding of these programs and pathways, the transcriptional and epigenetic profile of naïve, stem-cell like anti-tumor T cells and memory CD8+ T cells generated following different chronic virus infections will be compared. This will provide an integrated profile of long-term memory T cells that drive protection in the chronic setting. This approach will lead to the developmental transcriptional blueprint in which stable and protective CD8+ T cells memory is generated, even in shadow of immune dysregulation. The bioinformatics analysis will be focused on identifying unique components of CD8+ T cell memory machinery, as well as, identifying a unified core program that is conserved in multiple settings such as different virus infections and anti-tumor responses.

• DFG Programme: WBP Fellowship
• International Connection: Australia
• Host: Professorin Gabrielle Belz, Ph.D.