CD4 + T cells are homeostatic regulators during Mtb reinfection

  • Biology
  • Computational Methods
  • Immunology
  • Infectious Disease
  • Josh Bromley
  • Sarah Nyquist
  • Son Nguyen
  • Dennis Wang
  • Alex K. Shalek
  • Bromley et al.▾
    Bromley, J. D., Ganchua, S. K. C., Nyquist, S. K., Maiello, P., Chao, M., Borish, H. J., Rodgers, M., Tomko, J., Kracinovsky, K., Mugahid, D., Nguyen, S., Wang, D., Rosenberg, J. M., Klein, E. C., Gideon, H. P., Floyd-O'Sullivan, R., Berger, B,., Scanga, C. A., Lin, P. L., Fortune, S. M., Skalek, A.K., Flynn, J. L.
  • bioRxiv , Volume 12 , Issue 21
  • January, 2024
Biology
Computational Methods
Immunology
Infectious Disease
Josh Bromley
Sarah Nyquist
Son Nguyen
Dennis Wang
Alex K. Shalek

Abstract

Immunological priming – either in the context of 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. Here, using clinical and microbiological endpoints in a non-human primate reinfection model, we demonstrate that prior Mtb infection elicits a long-lasting protective response against subsequent Mtb exposure and that the depletion of CD4 + T cells prior to Mtb rechallenge significantly abrogates this protection. Leveraging microbiologic, PET-CT, flow cytometric, and single-cell RNA-seq data from primary infection, reinfection, and reinfection-CD4 + T cell depleted granulomas, we identify differential cellular and microbial features of control. The data collectively demonstrate that the presence of CD4 + T cells in the setting of reinfection results in a reduced inflammatory lung milieu characterized by reprogrammed CD8 + T cell activity, reduced neutrophilia, and blunted type-1 immune signaling among myeloid cells, mitigating Mtb disease severity. These results open avenues for developing vaccines and therapeutics that not only target CD4 + and CD8 + T cells, but also modulate innate immune cells to limit Mtb disease.

CD4 + T cells are homeostatic regulators during Mtb reinfection