Metabolic Regulation by SAPS3 of Virus-specific T cell Immunity

Chronic infections like HIV, HBC and HCV and cancers that evade the immune system continue to impact the lives of millions of patients worldwide causing high morbidity and mortality. It is now evident that during persistent antigen, CD8+ T cells become phenotypically and functionally exhausted. Continuous TCR stimulation, high expression of multiple inhibitory receptors, and multiple immunosuppressive mechanisms limit effector T cell functions. T cell exhaustion is observed in chronic infections in murine, monkey, and human hosts. Immune checkpoint blockade (ICB) can reinvigorate exhausted T cells and improve pathogen and tumor control in mice and patients. These drugs are now standard treatments for cancer, but at present are effective only in very few patients, highlighting the need to identify additional immunotherapies aimed to enhance the quality and quantity of the responding T cells to help improve patient outcomes. Our previous findings have identified Serine/threonine-protein phosphatase 6 (PP6) regulatory subunit 3 (SAPS3) as a negative regulator of AMPK. Preliminary data reveal that SAPS3 is highly expressed and upregulated on exhausted CD8+ T cells during infection. Mice with SAPS3 deletion exhibit increased frequencies and numbers of virus-specific CD8+ and CD4+ T cells, with enhanced functionality and increased mortality compared to wild-type (WT) mice following Cl13 infection. In addition, we found that inhibitor receptors were lower on virus-specific CD4+ and CD8+ T cells in Saps3-/- mice. Mechanistically, we observed increased AMPK activity and metabolism in Saps3-/- CD8+ T cells compared to WT only after Cl13 infection. Our data also showed that after acute LCMV Arm infection, Saps3-/- mice develop higher frequencies and numbers of functional CD8+ T cells. Based on our preliminary data, we plan to test the central hypothesis that SAPS3 is a key negative regulator of CD8+ T cells through regulation of AMPK and metabolism during chronic viral infection. The proposed research will provide a mechanistic analysis of how T cells are regulated during viral infection. We will test our hypothesis by pursuing the following three specific aims 1) To determine the role of SAPS3 in virus-specific T cells during acute and chronic viral infection 2) To elucidate the molecular mechanisms by which SAPS3 regulates T cell activation 3) To evaluate the therapeutic potential of combining Saps3 deletion and immune checkpoint blockade (ICB) in therapy sensitive vs resistant tumors. This contribution will be significant because understanding how metabolic regulators fundamentally function in T cells has the potential to lead to the development of therapeutic interventions targeting these pathways to modulate T cells and help prevent and/or treat patients with chronic infection, cancer, or autoimmunity. Project Number: 1R01AI187458-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Roberto Tinoco (+1 co-PI) | Institution: UNIVERSITY OF CALIFORNIA-IRVINE, IRVINE, CA | Award Amount: $2,832,747 | Activity Code: R01 | Study Section: Immunity and Host Defense Study Section[IHD] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI18745801A1