Sharpe, ArleneGleiberman, Annette2026-01-1320252026-01-052025Gleiberman, Annette. 2025. Investigating PD-1 regulation of CD8+ T cell fate following acute influenza infection. Masters Thesis, Harvard Medical School.32002849https://dash.harvard.edu/handle/1/42725129The cornerstone of the adaptive immune system is the capacity to remember and rapidly respond to previously encountered pathogens. Tissue-resident memory (TRM) CD8+ T cells represent a specialized subset of memory T cells that maintain permanent residence at common barrier tissues and enable rapid response to tissue perturbation upon re-encounter with antigen. Checkpoint receptors such as PD-1 have been heavily studied in the context of chronic antigen settings but are also known to be upregulated constitutively on TRM. However, the impact of PD-1 on the differentiation and function of CD8+ TRM cells following acute contexts is not well understood. This work explores how PD-1 signaling regulates the differentiation of CD8+ TRM cells following acute influenza infection. Genetic deletion of PD-1 in influenza-specific CD8+ T cells impaired acquisition of CD69 and CD103 – canonical TRM markers – at both effector and memory time points. Targeted deletion of an exhaustion-associated PD-1 enhancer region attenuated PD-1 expression in CD8+ T cells in flu-infected tissues, reducing tissue residency marker acquisition. Mouse models with germline or CD8-specific PD-1 loss had reduced tissue-residency marker expression within antigen-experienced CD8+ T cells. However, antibody blockade of the PD-1 pathway during priming did not recapitulate the TRM defects observed with genetic deletion. Our findings highlight PD-1's complex, context-dependent effects on CD8+ T cell fate decisions and establish its critical role in balancing protective immunity with tissue damage following respiratory viral infection.application/pdfenImmunologyThesis or Dissertation2026-01-130000-0002-4155-4224