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; Tyler D Bold

doi:10.1038/s41467-023-44152-8

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

Journal article

Open access

Peer reviewed

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, …

Nature communications, Vol.14(1), 8423

12/19/2023

DOI: 10.1038/s41467-023-44152-8

PMCID: PMC10728168

PMID: 38110410

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https://doi.org/10.1038/s41467-023-44152-8View

Published (Version of record) Open Access

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-GFP cells contain expanded TCR clonotypes, have elevated expression of co-stimulatory genes such as Tnfrsf4/OX40, and are functionally more protective than Nur77-GFP cells. By contrast, Nur77-GFP 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.

Immunotherapy

Animals

CD4-Positive T-Lymphocytes

CD8-Positive T-Lymphocytes

Humans

Mice

Receptors, OX40 - agonists

Tuberculosis - therapy

Details

Title: Subtitle: Recently activated CD4 T cells in tuberculosis express OX40 as a target for host-directed immunotherapy
Creators: 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 - Brighton and Sussex Medical School
David R Boulware - University of Minnesota
Tyler D Bold - University of Minnesota
Resource Type: Journal article
Publication Details: Nature communications, Vol.14(1), 8423
DOI: 10.1038/s41467-023-44152-8
PMID: 38110410
PMCID: PMC10728168
NLM abbreviation: Nat Commun
eISSN: 2041-1723
Grant note: R01 AI162786 / NIAID NIH HHS K08 AI150425 / NIAID NIH HHS T32 AI055433 / NIAID NIH HHS T32 HL007741 / NHLBI NIH HHS R01 AI173780 / NIAID NIH HHS
Language: English
Date published: 12/19/2023
Academic Unit: Pathology
Record Identifier: 9984533288402771

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