A Critical Role for CD8 T Cells in a Nonhuman Primate Model of Tuberculosis

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Abstract
The role of CD8 T cells in anti-tuberculosis immunity in humans remains unknown, and studies of CD8 T cell–mediated protection against tuberculosis in mice have yielded controversial results. Unlike mice, humans and nonhuman primates share a number of important features of the immune system that relate directly to the specificity and functions of CD8 T cells, such as the expression of group 1 CD1 proteins that are capable of presenting Mycobacterium tuberculosis lipids antigens and the cytotoxic/bactericidal protein granulysin. Employing a more relevant nonhuman primate model of human tuberculosis, we examined the contribution of BCG- or M. tuberculosis-elicited CD8 T cells to vaccine-induced immunity against tuberculosis. CD8 depletion compromised BCG vaccine-induced immune control of M. tuberculosis replication in the vaccinated rhesus macaques. Depletion of CD8 T cells in BCG-vaccinated rhesus macaques led to a significant decrease in the vaccine-induced immunity against tuberculosis. Consistently, depletion of CD8 T cells in rhesus macaques that had been previously infected with M. tuberculosis and cured by antibiotic therapy also resulted in a loss of anti-tuberculosis immunity upon M. tuberculosis re-infection. The current study demonstrates a major role for CD8 T cells in anti-tuberculosis immunity, and supports the view that CD8 T cells should be included in strategies for development of new tuberculosis vaccines and immunotherapeutics. Tuberculosis, HIV/AIDS and malaria remain top killers worldwide. Cell-mediated immune responses play a crucial role in immunity against tuberculosis. While CD4 T cells are well described for their protection against tuberculosis, little is known about the role of human CD8 T cells in anti-tuberculosis immunity. Studies done to date in mice have yielded conflicting results regarding the role of mouse CD8 T cells in tuberculosis. Since there are considerable differences in CD8 T cell biology between mice and primates including humans and macaques, studies in humans or macaques are crucial for clarifying human CD8 T cell–mediated immunity against tuberculosis. Thus, we used a macaque tuberculosis model to examine the contribution of CD8 T cells to vaccine-induced immunity against tuberculosis. We found that CD8 T cells play a role in BCG vaccine-induced immune control of Mycobacterium tuberculosis replication and in the vaccine-induced immunity against tuberculosis. Consistently, memory CD8 T cells also play a crucial role in anti-tuberculosis immunity upon M. tuberculosis re-infection. The findings in the current study provide evidence that human CD8 T cells are of importance for anti-tuberculosis immunity, and support the view that CD8 T cells should be targeted for development of new tuberculosis vaccines and immunotherapeutics.

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