Schober, J. | Search bioRxiv

bioRxiv2026

Protection against disseminated disease following reinfection with Mycobacterium tuberculosis requires CD8+ lymphocytes

Concomitant immunity is protective adaptive immunity conferred by pre-existing infection against subsequent exposures. This phenomenon is effective in the context of human tuberculosis (TB) and has been successfully recapitulated in non-human primates (NHPs). We previously demonstrated that depletion of CD4 T cells prior to secondary challenge with Mycobacterium tuberculosis (Mtb) only partially abrogated protection, implicating a critical role for additional cell types. Here, we describe the effects of depleting CD8 expressing cells in this model. CD4+ T cells in the airway were unable to compensate for lost cytotoxicity due to CD8 depletion. Contrary to the results of CD4 depletion, CD8 depleted animals exhibited a unique inability to limit Mtb dissemination, with significant lymph node involvement despite a short 4-week infection. These data suggest that concomitant immunity relies on non-redundant roles played by CD8+ lymphocytes. Thus, future vaccines should be designed to induce effective responses by both CD4+ and CD8+ populations to maximize efficacy.

immunology↗

bioRxiv2025

Antiretroviral treatment does not prevent extrapulmonary tuberculosis during SIV/Mtb co-infection in macaques

Co-infection with both HIV and M. tuberculosis (Mtb) results in disseminated tuberculosis (TB) and accelerated progression of HIV. Despite greater access to antiretroviral treatment (ART), it remains unclear whether suppression of HIV replication protects against severe Mtb infection. Here, using a macaque model of SIV/Mtb coinfection, we investigated whether treatment of SIV infection with ART influenced control of a subsequent Mtb challenge compared to SIV infected macaques who were not treated with ART. Using a macaque model of simian immunodeficiency virus (SIV)-Mtb co-infection, macaques were first infected with SIVB670, SIVB670 with ART, or saline followed by a low-dose Mtb inoculation with serial clinical, microbiological, PET CT imaging, and immunologic assessments. At necropsy, gross pathology, viremia, bacterial burden, and immunologic parameters were compared. SIV-TB animals had greater gross pathology and total bacterial burden than TB only and SIV/ART/TB groups. However, despite normal blood CD4 counts and undetectable SIV RNA, SIV/ART/TB macaques showed similar clinical parameters and extrapulmonary involvement as SIV/TB animals. Analysis of barcoded-Mtb suggests ART control of SIV replication does not prevent Mtb extrapulmonary dissemination. These data indicate that people living with HIV on ART remain at high risk of bacterial dissemination and extrapulmonary TB disease, particularly when methods to identify extrapulmonary disease are inconsistent. This highlights the importance of understanding the mechanism of extrapulmonary spread and disease severity in HIV/TB co-infected individuals.

immunology↗