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.
Little is known about the immune distribution and localization of antigen-specific T cells in mucosal interfaces of tissues/organs during infection of humans. In this study, we made use of a macaque model ofAccumulating evidence suggests that human ␥␦ T cells belong to nonclassical T cells that contribute to both innate and adaptive immune responses. Resident ␥␦ T cells within epithelia make up a portion of intraepithelial lymphocytes and may play a role in innate immunity against microbial invasions, immune surveillance of malignances, and even skin repair after damage (1, 16). Peripheral ␥␦ T cells circulating in the blood and lymphoid tissues appear to behave as both innate and adaptive immune cells (1, 5, 9, 16). Circulating V␥2V␦2 T cells exist only in primates and, in humans, constitute 60 to 95% of total blood ␥␦ T cells. Recent studies suggest that circulating V␥2V␦2 T cells in primates can recognize phosphoantigens from some bacteria, such as Mycobacterium tuberculosis, and possess both innate and adaptive immune features (1, 5, 9, 16). The finding that "unprimed" V␥2V␦2 T cells can recognize and react to wide ranges of nonpeptide ligands with the capability of "naïve" production of cytokines has been interpreted as a pattern recognition-like feature of innate immune cells.On the other hand, the capacity of V␥2V␦2 T cells to undergo major clonal expansion in primary infection and to mount rapid recall expansion upon reinfection has been proposed as an adaptive (memory-type) immune response of these ␥␦ T cells (5). Consistent with these memory-type responses is the demonstration of memory phenotypes of V␥2V␦2 T cells in the blood of humans (7).Tuberculosis (TB) is the second leading cause of death worldwide, killing about 1.8 million persons annually. While human CD4 T cells play a crucial role in immune protection against M. tuberculosis infection, other T-cell populations, including V␥2V␦2 T cells, are poorly characterized regarding their roles in immunity to TB. We recently demonstrated that Mycobacterium bovis BCG-vaccinated monkeys can mount memory-type immune responses of V␥2V␦2 T cells in the pulmonary compartment following M. tuberculosis infection by aerosol and that the rapid recall responses of these ␥␦ T cells coincide with protection against acutely fatal TB in juvenile rhesus monkeys (19). Nevertheless, immune responses of V␥2V␦2 T cells in patients with chronic TB appear to be suppressed (for a review, see reference 4). It has been debated whether the depression of the V␥2V␦2 T-cell response in TB is caused by the infection or allows the infection to progress (4). Further studies are needed to elucidate the biology and effector function of V␥2V␦2 T cells in M. tuberculosis infection.
The immune mechanisms by which early host-mycobacterium interaction leads to the development of severe tuberculosis (TB) remain poorly characterized in humans. Here, we demonstrate that severe TB in juvenile rhesus monkeys down-regulated many genes in the blood but up-regulated selected genes constituting gene networks of Th17 and Th1 responses, T cell activation and migration, and inflammation and chemoattractants in the pulmonary and lymphoid compartments. Overexpression (450–2740-fold) of 13 genes encoding inflammatory cytokines and receptors (IL-22, CCL27, MIP-1α, IP-10, CCR4, CCR5, and CXCR3), immune dysfunctional receptors and ligands (PD1 and PDL2), and immune activation elements (IL-3, IFN-β, TIM1, and TLR2) was seen in tissues, with low antigen-specific cellular responses. Thus, severe TB in macaques features unbalanced up-regulation of immune-gene networks without proportional increases in antigen-specific cellular responses.
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