Recently activated CD4 T cells in tuberculosis express OX40 as a target for host-directed immunotherapy

Abigail R. Gress, Christine E. Ronayne, Joshua M. Thiede, David K. Meyerholz, Samuel Okurut, Julia Stumpf, Tailor V. Mathes, Kenneth Ssebambulidde, David B. Meya, Fiona V. Cresswell, David R. Boulware and Tyler D. Bold ()
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Abigail R. Gress: University of Minnesota
Christine E. Ronayne: University of Minnesota
Joshua M. Thiede: University of Minnesota
David K. Meyerholz: University of Iowa
Samuel Okurut: Makerere University
Julia Stumpf: University of Minnesota
Tailor V. Mathes: University of Minnesota
Kenneth Ssebambulidde: Makerere University
David B. Meya: Makerere University
Fiona V. Cresswell: Makerere University
David R. Boulware: University of Minnesota
Tyler D. Bold: University of Minnesota

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-44152-8

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