Intravenous BCG-mediated protection against tuberculosis requires CD4+ T cells and CD8alpha+ lymphocytes

Andrew W. Simonson, Joseph J. Zeppa, Allison N. Bucsan, Michael C. Chao, Supriya Pokkali, Forrest Hopkins, Michael R. Chase, Andrew J. Vickers, Matthew S. Sutton, Caylin G. Winchell, Amy J. Myers, Cassaundra L. Ameel, Ryan Kelly, Ben Krouse, Luke E. Hood, Jiaxiang Li, Chelsea C. Lehman, Megha Kamath, Jaime Tomko, Mark A. Rodgers, Rachel Donlan, Harris Chishti, H. Jacob Borish, Edwin Klein, Charles A. Scanga, Sarah Fortune, Philana Ling Lin, Pauline Maiello, Mario Roederer, Patricia A. Darrah, Robert A. Seder, JoAnne L. Flynn

The raw flow cytometry data associated with the study can be made available upon request. Its collection predates the beginning of the consortium spanning an extended period of time, and numerous personnel. The Analyzed flow data is available here: https://fairdomhub.org/data_files/7915

DOI: https://doi.org/10.1084/jem.20241571

Abstract:

Tuberculosis (TB) is a major health burden worldwide despite widespread intradermal (ID) BCG vaccination in newborns. We previously demonstrated that changing the BCG route and dose from 5 × 105 CFUs ID to 5 × 107 CFUs i.v. resulted in prevention of Mycobacterium tuberculosis (Mtb) infection and TB disease in highly susceptible nonhuman primates. Identifying immune mechanisms protection following i.v. BCG will facilitate development of more effective vaccines against TB. Here, we depleted lymphocyte subsets prior to and during Mtb challenge in i.v. BCG-vaccinated macaques to identify those necessary for protection. Depletion of adaptive CD4 T cells, but not adaptive CD8αβ T cells, resulted in loss of protection with increased Mtb burdens and dissemination, indicating that CD4 T cells are critical to i.v. BCG-mediated protection. Depletion of unconventional CD8α-expressing lymphocytes (NK cells, innate T cells, and CD4+CD8α+ double-positive T cells) abrogated protection in most i.v. BCG-immunized macaques, supporting further investigation into which of these cell subsets contribute to protection after vaccination.