To examine the role of T cell receptor (TCR) in gammadelta T cells in adaptive immunity, a macaque model was used to follow Vgamma2Vdelta2+ T cell responses to mycobacterial infections. These phosphoantigen-specific gammadelta T cells displayed major expansion during Mycobacterium bovis Bacille Calmette-Guérin (BCG) infection and a clear memory-type response after BCG reinfection. Primary and recall expansions of Vgamma2Vdelta2+ T cells were also seen during Mycobacterium tuberculosis infection of naive and BCG-vaccinated macaques, respectively. This capacity to rapidly expand coincided with a clearance of BCG bacteremia and immunity to fatal tuberculosis in BCG-vaccinated macaques. Thus, Vgamma2Vdelta2+ T cells may contribute to adaptive immunity to mycobacterial infections.

Dominant Vγ2Vδ2 T-cell subset exist only in primates, and recognize phosphoantigen from selected pathogens including M. tuberculosis(Mtb). In vivo function of Vγ2Vδ2 T cells in tuberculosis remains unknown. We conducted mechanistic studies to determine whether earlier expansion/differentiation of Vγ2Vδ2 T cells during Mtb infection could increase immune resistance to tuberculosis in macaques. Phosphoantigen/IL-2 administration specifically induced major expansion and pulmonary trafficking/accumulation of phosphoantigen-specific Vγ2Vδ2 T cells, significantly reduced Mtb burdens and attenuated tuberculosis lesions in lung tissues compared to saline/BSA or IL-2 controls. Expanded Vγ2Vδ2 T cells differentiated into multifunctional effector subpopulations capable of producing anti-TB cytokines IFNγ, perforin and granulysin, and co-producing perforin/granulysin in lung tissue. Mechanistically, perforin/granulysin-producing Vγ2Vδ2 T cells limited intracellular Mtb growth, and macaque granulysin had Mtb-bactericidal effect, and inhibited intracellular Mtb in presence of perforin. Furthermore, phosphoantigen/IL2-expanded Vγ2Vδ2 T effector cells produced IL-12, and their expansion/differentiation led to enhanced pulmonary responses of peptide-specific CD4+/CD8+ Th1-like cells. These results provide first in vivo evidence implicating that early expansion/differentiation of Vγ2Vδ2 T effector cells during Mtb infection increases resistance to tuberculosis. Thus, data support a rationale for conducting further studies of the γδ T-cell-targeted treatment of established TB, which might ultimately help explore single or adjunctive phosphoantigen expansion of Vγ2Vδ2 T-cell subset as intervention of MDR-tuberculosis or HIV-related tuberculosis.

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.