Phosphoantigen/IL2 Expansion and Differentiation of Vγ2Vδ2 T Cells Increase Resistance to Tuberculosis in Nonhuman Primates

Abstract

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.

Pathogenic Events in a Nonhuman Primate Model of Oral Poliovirus Infection Leading to Paralytic Poliomyelitis

“…The central nervous system, including brain, brain stem, and spinal cord, and the gastrointestinal tract, including tonsil, small and large intestines, mesenteric lymph nodes, and other major organs, were collected, examined, and processed for histology analysis. Histopathologic lesions were determined using digital scans to record total pixel counts on hematoxylin and eosin (H&E)-stained sections, and the specimen area was measured in square centimeters using Image-Pro Plus software (Media Cybernetics, Silver Spring, MD), as we previously described (26,27). Histopathologic lesions in the spinal cord and other CNS tissues were measured in the reference poliomyelitis scores described in the WHO protocol (28).…”

“…The multivariate analysis of variance (ANOVA) and nonparametric t test were used, as previously described (27).…”

Long noncoding RNA derived from CD244 signaling epigenetically controls CD8 + T-cell immune responses in tuberculosis infection

“…CD4 + T cells, CD8 + T cells, and γδ T cells played critical roles in mounting adaptive immune response against MTB infection (3)(4)(5)(6)(7)(8). Deciphering the molecular mechanisms for host responses linked to TB pathogenesis and prognosis is of great importance for developing new vaccines and therapeutics and for diagnosis.…”

Monkey Models of Tuberculosis: Lessons Learned

“…A series of subsequent investigations were dedicated to macaque research to assess novel TB vaccines and drugs, as well as to gain an understanding of the pathogenesis of M. tuberculosis infection and reactivation. Figures 2 and 3 abridge the RM (13,(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43) and CM (10,15,25,(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59) models of experimental M. tuberculosis infection after the Golden Age, from 2001 to 2014.…”