Gress, Abigail2023-11-302023-11-302023-09https://hdl.handle.net/11299/258867University of Minnesota Ph.D. dissertation. September 2023. Major: Microbiology, Immunology and Cancer Biology. Advisor: Tyler Bold. 1 computer file (PDF); xi, 128 pages.After Mycobacterium tuberculosis (Mtb) infection millions of effector T cells traffic to the lungs, but relatively few find antigen and become activated. We used an antigen receptor reporter mouse (Nur77-GFP) infected with Mtb to distinguish recently activated CD4 T cells from others in the lungs. Recently activated Nur77-GFPHI cells more often expressed protective markers and were enriched for expanded TCR clonotypes. Nur77-GFPHI cells differentially expressed co-stimulatory genes including Tnfrsf4/OX40 and were functionally more protective than Nur77-GFPLO. Nur77-GFPLO cells more often expressed markers of terminal exhaustion, cytotoxicity, and the trafficking receptor S1pr5, associated with vascular localization. A short course of immunotherapy with an agonist monoclonal antibody targeting OX40+ cells during early infection transiently expanded CD4 T cell numbers and shifted their phenotype towards parenchymal protective cells, which decreased the lung bacterial burden and extended host survival, offering an additive benefit to antibiotics. We have newly identified OX40 as a conserved marker of recently activated CD4 T cells at the infection site and a target for immunotherapy in tuberculosis.enImmunologyImmunotherapyOX40SequencingT cellsTuberculosisThesis or Dissertation