Developmental acquisition of memory-phenotype CD8+ T cell function in infection and cancer

/ABSTRACT In unprimed specific pathogen free and germ-free mice, there exists a population of αβ CD8+ T-cells that exhibit hallmarks of agonist ligand encounter, termed CD8 memory phenotype (CD8-MP) cells. These cells account for ~10% of the CD8+ T cell repertoire in adult mice, have a CD44hiCD122+ phenotype, display other memory markers shared by ‘true memory’ CD8+ T cells (CD8-TM) generated in response to pathogen challenge, and have incompletely defined functions. Previously, CD8-MP cells were thought to develop in the periphery due to subthreshold T-cell receptor (TCR) signaling to non-cognate self-antigen and in response to cytokine signaling. However, recent work from our lab demonstrated that CD8-MP differentiation is a robust and conserved TCR- instructed process driven by the recognition of agonist self-ligands in the thymus and consolidated in the periphery. Importantly, we also demonstrated that select CD8-MP-biased clones are recurrently enriched in oncogene-driven prostate tumors and express high densities of PD-1, suggesting a previously unappreciated role for CD8-MP cells in the immune response to cancer. The objective of this proposal is to define the immunological mechanisms driving the differentiation of CD8-MP cells and the functional potential imparted by this process by analyzing CD8-MP functional activity in settings of infection and cancer. We will test the hypothesis that the differentiation of CD8-MP cells is a two-step process, triggered by the recognition of self- pMHC-I antigen displayed by medullary thymic epithelial cells (mTECs), followed by sensing of MHC-I and IL- 15 in the periphery, which confer CD8-MP cells with a unique “non-cytolytic” functional profile. In Aim 1, we will define the antigen presenting cells and accessory signals directing the differentiation of CD8-MP cells at both a polyclonal and monoclonal level, utilizing our TCR “retrogenic” mouse pipeline and our previously identified naturally occurring CD8-MP biased clones. In Aim 2, we will identify CD8-naïve and CD8-MP-biased clones reactive to the same model antigen and utilize our TCRrg pipeline to interrogate the function of these cells following agonist ligand encounter in a tumor model and in other inflammatory contexts. Elucidating these mechanisms will provide needed insight into the biology of this prevalent T cell subset and will have key implications for our understanding of self-tolerance and cancer. Project Number: 5F30AI183709-02 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Nikita Maheshwari | Institution: UNIVERSITY OF CHICAGO, CHICAGO, IL | Award Amount: $55,114 | Activity Code: F30 | Study Section: Special Emphasis Panel[ZRG1-F07B-G(20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/5F30AI18370902