CD8+ lymphocytes are critical for early control of tuberculosis in macaques

Author:

Winchell Caylin G.123ORCID,Nyquist Sarah K.4567ORCID,Chao Michael C.8ORCID,Maiello Pauline13ORCID,Myers Amy J.13ORCID,Hopkins Forrest8ORCID,Chase Michael8ORCID,Gideon Hannah P.13ORCID,Patel Kush V.13ORCID,Bromley Joshua D.4567ORCID,Simonson Andrew W.13ORCID,Floyd-O’Sullivan Roisin56ORCID,Wadsworth Marc56ORCID,Rosenberg Jacob M.89ORCID,Uddin Rockib9ORCID,Hughes Travis56ORCID,Kelly Ryan J.13ORCID,Griffo Josephine1ORCID,Tomko Jaime13ORCID,Klein Edwin10ORCID,Berger Bonnie57ORCID,Scanga Charles A.13ORCID,Mattila Joshua11ORCID,Fortune Sarah M.5812ORCID,Shalek Alex K.56712ORCID,Lin Philana Ling313ORCID,Flynn JoAnne L.13ORCID

Affiliation:

1. University of Pittsburgh School of Medicine 1 Department of Microbiology and Molecular Genetics, , Pittsburgh, PA, USA

2. Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine 2 Division of Pulmonary, , Pittsburgh, PA, USA

3. Center for Vaccine Research, University of Pittsburgh School of Medicine 3 , Pittsburgh, PA, USA

4. Program in Computational and Systems Biology, Massachusetts Institute of Technology 4 , Cambridge, MA, USA

5. Broad Institute, Harvard University and Massachusetts Institute of Technology 5 , Cambridge, MA, USA

6. Institute for Medical Engineering and Science, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT) 6 Department of Chemistry, , Cambridge, MA, USA

7. MIT 7 Computer Science and Artificial Intelligence Laboratory and Department of Mathematics, , Cambridge, MA, USA

8. Harvard T. H. Chan School of Public Health 8 Department of Immunology and Infectious Diseases, , Boston, MA, USA

9. Massachusetts General Hospital 9 Division of Infectious Diseases, Department of Medicine, , Boston, MA, USA

10. University of Pittsburgh 10 Division of Laboratory Animal Research, , Pittsburgh, PA, USA

11. Graduate School of Public Health, University of Pittsburgh 11 Department of Infectious Disease and Microbiology, , Pittsburgh, PA, USA

12. Ragon Institute of MGH, MIT, and Harvard 12 , Cambridge, MA, USA

13. Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine 13 Department of Pediatrics, , Pittsburgh, PA, USA

Abstract

The functional role of CD8+ lymphocytes in tuberculosis remains poorly understood. We depleted innate and/or adaptive CD8+ lymphocytes in macaques and showed that loss of all CD8α+ cells (using anti-CD8α antibody) significantly impaired early control of Mycobacterium tuberculosis (Mtb) infection, leading to increased granulomas, lung inflammation, and bacterial burden. Analysis of barcoded Mtb from infected macaques demonstrated that depletion of all CD8+ lymphocytes allowed increased establishment of Mtb in lungs and dissemination within lungs and to lymph nodes, while depletion of only adaptive CD8+ T cells (with anti-CD8β antibody) worsened bacterial control in lymph nodes. Flow cytometry and single-cell RNA sequencing revealed polyfunctional cytotoxic CD8+ lymphocytes in control granulomas, while CD8-depleted animals were unexpectedly enriched in CD4 and γδ T cells adopting incomplete cytotoxic signatures. Ligand-receptor analyses identified IL-15 signaling in granulomas as a driver of cytotoxic T cells. These data support that CD8+ lymphocytes are required for early protection against Mtb and suggest polyfunctional cytotoxic responses as a vaccine target.

Funder

National Institutes of Health

National Institute of Allergy and Infectious Diseases

National Heart, Lung, and Blood Institute

Bill and Melinda Gates Foundation

Harvard University Center for AIDS Research

Harvard Clinical and Translational Science Center

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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