UC San Diego

Infectious diseases are a worldwide problem that have been brought into focus by the 2020 SARS-CoV-22020 outbreak. The respiratory coronavirus is responsible for a global pandemic that has claimed over 6 million lives and affected hundreds of millions more. To slow the spread of the infection and ease the strain on healthcare systems, new vaccines and therapeutics were developed that protected against severe diseases. However, multiple waves of new variants emerged as the virus evolved to escape immunity afforded by vaccination attempts. To generate more effective vaccines that would provide life-long, pan-variant protection against infectious pathogens, we must first understand the immune response and the memory cells that confer immunity.Following infection, memory CD8 T cells can be found surveilling the body in circulation or persisting in the tissues. In the circulating compartment, different subsets of memory CD8 T cells have been identified based on localization pattern, phenotype, and function. Effector memory T cells (TEM) can be found traversing the non-lymphoid organs and are of high effector function, low proliferative, and low differentiation potentials. Central memory T cells (TCM), however, home to the secondary lymphoid tissues and are of low effector function but high differentiation potential. The distinction between memory CD8 T cell subsets is important not only for understanding the immune response, but also for predicting T cell protection post infection or vaccination. While TCM cells are homogeneous based of expression of cell surface markers, several studies have reported heterogeneity within the TEM population. We found that the conventional definition of TEM cells is conflated with a terminally-differentiated (t-TEM) subset, which consists of memory T cells with effector characteristics. The t-TEM population is of distinct ontogeny and fate from TEM and TCM. All three subsets differentially rely on key lineage-defining transcription factors and are transcriptionally and functionally distinct. In human blood, we identified analogous subsets with corresponding cell surface molecules and gene expression patterns. The delineation of t-TEM further clarified our understanding of circulating memory CD8 T cell biology. Through the characterization of memory CD8 T cell subsets, we observed a subset- and tissue-specific expression of granzyme A (GzmA), a serine protease that can induce apoptosis as well as mediate cytokine production. We showed that expression of GzmA by t-TEM in the circulation and tissue-resident (TRM) T cells in the intestines conferred heightened protection against viral reinfections. However, CD8 T cell-specific GzmA in the colon can contribute to pathology in the DSS-induced model of colitis. In addition to enhancing cell-death, GzmA can also mediate in inflammatory cytokine response in vitro and in vivo. Together, these studies clarified the definition of memory T cell subsets and provided insights on the role of CD8 T cell-dependent GzmA in conferring immunity against reinfection as well as contributing to inflammation.