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.

Details

Title
Recently activated CD4 T cells in tuberculosis express OX40 as a target for host-directed immunotherapy
Author
Gress, Abigail R. 1 ; Ronayne, Christine E. 1 ; Thiede, Joshua M. 1   VIAFID ORCID Logo  ; Meyerholz, David K. 2   VIAFID ORCID Logo  ; Okurut, Samuel 3   VIAFID ORCID Logo  ; Stumpf, Julia 4 ; Mathes, Tailor V. 1   VIAFID ORCID Logo  ; Ssebambulidde, Kenneth 3   VIAFID ORCID Logo  ; Meya, David B. 3 ; Cresswell, Fiona V. 5   VIAFID ORCID Logo  ; Boulware, David R. 4   VIAFID ORCID Logo  ; Bold, Tyler D. 1   VIAFID ORCID Logo 

 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) 
 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) 
 Makerere University, Infectious Diseases Institute, P.O. Box 22418, Kampala, Uganda (GRID:grid.11194.3c) (ISNI:0000 0004 0620 0548) 
 University of Minnesota, Department of Medicine, Minneapolis, USA (GRID:grid.17635.36) (ISNI:0000 0004 1936 8657) 
 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) 
Pages
8423
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2903127632
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.