Immune Distribution and Localization of Phosphoantigen-Specific Vγ2Vδ2 T Cells in Lymphoid and Nonlymphoid Tissues inMycobacterium tuberculosisInfection

Abstract

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.

Cross-presenting human γδ T cells induce robust CD8 + αβ T cell responses

“…Importantly, transition from resting to fully activated V␥9V␦2 ϩ T cells (termed ␥␦ T-APCs) is associated with the expression of CCR7 that enables lymph node homing and a plethora of antigen-presentation and costimulation molecules (10,26). It is uncertain where in the human body antigen presentation by ␥␦ T-APCs may take place, but possible sites include the site of microbial encounter in peripheral tissues and infection draining lymphoid tissues (9,10,25,(27)(28)(29).…”

Antigen-specific Vγ2Vδ2 T effector cells confer homeostatic protection against pneumonic plaque lesions

“…S3). V␥2V␦2 T cells are not detectable in lung tissues of healthy uninfected macaques (22). Immunofluorescent Staining and Flow Cytometric Analysis.…”

“…We presume that a 5-h delay after inhalational Y. pestis infection would be a practical time point in which to determine whether HMBPP/IL-2 treatment could induce activation of V␥2V␦2 T cells and attenuation of inhalation plague. Thus, 12 cynomolgus macaques were infected with Y. pestis by aerosol using the head-only challenging system as described (1,22). Five hours after the inhalational Y. pestis infection, 6 macaques were treated with single-dose (50 mg/kg) HMBPP plus IL-2 treatment (17); 6 other animals were treated as controls with glucose plus IL-2 or glucose only (Table 1).…”

“…Complete necropsy was done for each of Y. pestis-infected monkeys as described (1,22). Animals were killed by i.v.…”

γδ-T cells: an unpolished sword in human anti-infection immunity

“…23 Another advantage of cd-T cell-based therapy relies on their ability to traffic to local sites of infection. 143,152 Moreover, the APC function of cd-T cells further favors their application in inducing antigen-specific immune responses to efficiently eliminate pathogens. 153 Finally, over 40 years of bisphosphonate usage in the clinic offers abundant references for their use in expanding and activating cd-T cells in vivo, although attention must still be paid to the mild or moderate acute responses evoked by their injection.…”