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Abstract
After Mycobacterium tuberculosis (Mtb) infection, many effector T cells traffic to the lungs, but few become activated. Here we use an antigen receptor reporter mouse (Nur77-GFP) to identify recently activated CD4 T cells in the lungs. These Nur77-GFPHI cells contain expanded TCR clonotypes, have elevated expression of co-stimulatory genes such as Tnfrsf4/OX40, and are functionally more protective than Nur77-GFPLO cells. By contrast, Nur77-GFPLO cells express markers of terminal exhaustion and cytotoxicity, and the trafficking receptor S1pr5, associated with vascular localization. A short course of immunotherapy targeting OX40+ cells transiently expands CD4 T cell numbers and shifts their phenotype towards parenchymal protective cells. Moreover, OX40 agonist immunotherapy decreases the lung bacterial burden and extends host survival, offering an additive benefit to antibiotics. CD4 T cells from the cerebrospinal fluid of humans with HIV-associated tuberculous meningitis commonly express surface OX40 protein, while CD8 T cells do not. Our data thus propose OX40 as a marker of recently activated CD4 T cells at the infection site and a potential target for immunotherapy in tuberculosis.
Marking of recently activated T cells may help further our understanding of immunity against Mycobacterium tuberculosis (Mtb). Here the authors use Nur77-GFP reporter mice infected with Mtb and systems data approaches to implicate OX40 as a marker for recently activated, functionally and transcriptome-wise distinct CD4 T cells, and as a potential target for immunotherapy.
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1 University of Minnesota, Department of Medicine, Minneapolis, USA (GRID:grid.17635.36) (ISNI:0000 0004 1936 8657); University of Minnesota, Center for Immunology, 2101 6th St SE, WMBB 2-118, Minneapolis, USA (GRID:grid.17635.36) (ISNI:0000 0004 1936 8657)
2 University of Iowa, Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, 1165 Medical Laboratories (ML), 51 Newton Rd, Iowa City, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294)
3 Makerere University, Infectious Diseases Institute, P.O. Box 22418, Kampala, Uganda (GRID:grid.11194.3c) (ISNI:0000 0004 0620 0548)
4 University of Minnesota, Department of Medicine, Minneapolis, USA (GRID:grid.17635.36) (ISNI:0000 0004 1936 8657)
5 Makerere University, Infectious Diseases Institute, P.O. Box 22418, Kampala, Uganda (GRID:grid.11194.3c) (ISNI:0000 0004 0620 0548); MRC/UVRI and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda (GRID:grid.11194.3c); Brighton and Sussex Medical School, Department of Global Health and Infection, Brighton, UK (GRID:grid.414601.6) (ISNI:0000 0000 8853 076X)