{Reference Type}: Journal Article
{Title}: Recently activated CD4 T cells in tuberculosis express OX40 as a target for host-directed immunotherapy.
{Author}: Gress AR;Ronayne CE;Thiede JM;Meyerholz DK;Okurut S;Stumpf J;Mathes TV;Ssebambulidde K;Meya DB;Cresswell FV;Boulware DR;Bold TD;
{Journal}: Nat Commun
{Volume}: 14
{Issue}: 1
{Year}: 2023 Dec 19
{Factor}: 17.694
{DOI}: 10.1038/s41467-023-44152-8
{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.