CD4+ T cells re-wire granuloma cellularity and regulatory networks to promote immunomodulation following Mtb reinfection

Joshua D Bromley; Sharie Keanne C Ganchua; Sarah K Nyquist; Pauline Maiello; Michael Chao; H Jacob Borish; Mark Rodgers; Jaime Tomko; Kara Kracinovsky; Douaa Mugahid; Son Nguyen; Qianchang Dennis Wang; Jacob M Rosenberg; Edwin C Klein; Hannah P Gideon; Roisin Floyd-O'Sullivan; Bonnie Berger; Charles A Scanga; Philana Ling Lin; Sarah M Fortune; Alex K Shalek; JoAnne L Flynn

doi:10.1016/j.immuni.2024.08.002

CD4⁺ T cells re-wire granuloma cellularity and regulatory networks to promote immunomodulation following Mtb reinfection

Immunity. 2024 Oct 8;57(10):2380-2398.e6. doi: 10.1016/j.immuni.2024.08.002. Epub 2024 Aug 29.

Authors

Joshua D Bromley¹, Sharie Keanne C Ganchua², Sarah K Nyquist³, Pauline Maiello⁴, Michael Chao⁵, H Jacob Borish², Mark Rodgers², Jaime Tomko², Kara Kracinovsky², Douaa Mugahid⁵, Son Nguyen⁶, Qianchang Dennis Wang⁷, Jacob M Rosenberg⁵, Edwin C Klein⁸, Hannah P Gideon², Roisin Floyd-O'Sullivan⁶, Bonnie Berger⁹, Charles A Scanga², Philana Ling Lin¹⁰, Sarah M Fortune¹¹, Alex K Shalek¹², JoAnne L Flynn¹³

Affiliations

¹ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Institute for Medical Engineering and Science (IMES), Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Graduate Program in Microbiology, Massachusetts Institute of Technology, Cambridge, MA, USA.
² Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA.
³ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Institute for Medical Engineering and Science (IMES), Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁵ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁶ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Institute for Medical Engineering and Science (IMES), Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁷ Institute for Medical Engineering and Science (IMES), Massachusetts Institute of Technology, Cambridge, MA, USA.
⁸ Division of Laboratory Animal Research, University of Pittsburgh, Pittsburgh, PA, USA.
⁹ Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰ Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹¹ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address: [email protected].
¹² Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Institute for Medical Engineering and Science (IMES), Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: [email protected].
¹³ Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: [email protected].

Abstract

Immunological priming-in the context of either prior infection or vaccination-elicits protective responses against subsequent Mycobacterium tuberculosis (Mtb) infection. However, the changes that occur in the lung cellular milieu post-primary Mtb infection and their contributions to protection upon reinfection remain poorly understood. Using clinical and microbiological endpoints in a non-human primate reinfection model, we demonstrated that prior Mtb infection elicited a long-lasting protective response against subsequent Mtb exposure and was CD4⁺ T cell dependent. By analyzing data from primary infection, reinfection, and reinfection-CD4⁺ T cell-depleted granulomas, we found that the presence of CD4⁺ T cells during reinfection resulted in a less inflammatory lung milieu characterized by reprogrammed CD8⁺ T cells, reduced neutrophilia, and blunted type 1 immune signaling among myeloid cells. These results open avenues for developing vaccines and therapeutics that not only target lymphocytes but also modulate innate immune cells to limit tuberculosis (TB) disease.

Keywords: CD4 T cells; CD4 depletion; CD8 T cells; Mycobacterium tuberculosis; concomitant immunity; granuloma; macaque; non-human primate; reinfection; single-cell RNA sequencing.

MeSH terms

Animals
CD4-Positive T-Lymphocytes* / immunology
CD8-Positive T-Lymphocytes* / immunology
Disease Models, Animal
Granuloma* / immunology
Granuloma* / microbiology
Humans
Immunomodulation*
Lung / immunology
Lung / microbiology
Lung / pathology
Mycobacterium tuberculosis* / immunology
Reinfection* / immunology
Tuberculosis / immunology
Tuberculosis / microbiology
Tuberculosis, Pulmonary / immunology
Tuberculosis, Pulmonary / microbiology

Grants and funding

T32 AI007387/AI/NIAID NIH HHS/United States