Distinct protective roles of CD4 and CD8 T cells in vaccine-mediated immunity against Mycobacterium tuberculosis

Abstract

Despite widespread vaccination with Bacille Calmette-Guerin (BCG) globally, tuberculosis (TB) remains a major global health concern. A new vaccine is urgently needed, but our limited understanding of immunity against Mycobacterium tuberculosis (Mtb) infection is a major barrier to designing more effective vaccines. Mice are commonly used to study TB immunity but deficiencies in the current conventional dose (CD) (50-100 CFU) mouse model have left little confidence in its translation to humans. Our lab has overcome these limitations by developing a physiologic ultra-low dose (ULD) (1-3 CFUs) Mtb infection, which resembles several aspects of human Mtb infection. Here, we assess vaccine-mediated protection using the ULD model and identify three parameters of BCG-mediated protection: 1. Durable reduction in overall lung burden, 2. Prevention of dissemination to the contralateral lung, and 3. Prevention of detectable infection in a subset of BCG vaccinated mice. Importantly, this is the first evidence that BCG vaccination can mediate sterilizing immunity in any mouse model of TB. Next, we sought to determine the lymphocyte subsets responsible for BCG-mediated immunity. We investigated the impact of BCG vaccination on early Mtb immunity before confounding differences in bacterial burden occurred. We found that BCG induced a robust effector CD4 and CD8 T cell response in the lung during early Mtb infection while changes in lung B cells were less pronounced. Furthermore, T cell depletion reversed the protection conferred by BCG, whereas B cell deficiency had no effect. Finally, we assessed the relative roles of CD4 and CD8 T cells in BCG-mediated immunity and found that CD4 and CD8 T cells promoted distinct aspects of immunity. CD4 T cells played larger roles in control of lung burden and prevention of dissemination to the contralateral lung, whereas CD8 T cells were more important for prevention of infection and played a minor role in control of lung burden. These newfound roles of CD8 T cells in BCG-mediated protection were masked using the supraphysiologic conventional dose challenge and could only be detected in the ULD model. Together, these studies further our understanding of vaccine-mediated protection against Mtb and highlight the ULD model as a superior platform for pre-clinical vaccine testing. Additionally, our work demonstrates distinct roles for CD4 and CD8 T cells in vaccine-mediated immunity. Targeting both aspects of immunity could be key to designing a more effective TB vaccine.