γδ T Cell Immune Manipulation during Chronic Phase of Simian HIV Infection Confers Immunological Benefits

Abstract

Vγ2Vδ2 T cells, a major human γδ T cell subset, recognize the phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) produced by mycobacteria and some opportunistic pathogens, and they contribute to innate/adaptive/homeostatic and anticancer immunity. As initial efforts to explore Vγ2Vδ2 T cell-based therapeutics against HIV/AIDS-associated bacterial/protozoal infections and neoplasms, we investigated whether a well-defined HMBPP/IL-2 therapeutic regimen could overcome HIV-mediated immune suppression to massively expand polyfunctional Vγ2Vδ2 T cells, and whether such activation/expansion could impact AIDS pathogenesis in simian HIV (SHIV)-infected Chinese rhesus macaques. While HMBPP/IL-2 coadministration during acute or chronic phase of SHIV infection induced massive activation/expansion of Vγ2Vδ2 T cells, the consequences of such activation/expansions were different between these two treatment settings. HMBPP/IL-2 cotreatment during acute SHIV infection did not prevent the increases in peak and set-point viral loads or the accelerated disease progression seen with IL-2 treatment alone. In contrast, HMBPP/IL-2 cotreatment during chronic infection did not exacerbate disease, and more importantly it could confer immunological benefits. Surprisingly, although viral antigenic loads were not increased upon HMBPP/IL-2 cotreatment during chronic SHIV infection, HMBPP activation of Vγ2Vδ2 T cells boosted HIV Env-specific Ab titers. Such increases in Abs were sustained for >170 days and were immediately preceded by increased production of IFN-γ, TNF-α, IL-4, and IL-10 during peak expansion of Vγ2Vδ2 T cells displaying memory phenotypes, as well as the short-term increased effector function of Vγ2Vδ2 T cells and CD4+ and CD8+ αβ T cells producing antimicrobial cytokines. Thus, HMBPP/Vγ2Vδ2 T cell-based intervention may potentially be useful for combating neoplasms and HMBPP-producing opportunistic pathogens in chronically HIV-infected individuals.

Primary MHC-Class II+ Cells Are Necessary To Promote Resting Vδ2 Cell Expansion in Response to (E)-4-Hydroxy-3-Methyl-But-2-Enyl-Pyrophosphate and Isopentenyl Pyrophosphate

“…It was previously reported that HMBPP and IL-2 treatment during simian-HIV infection in vivo was associated with the increased production of IFN-g, TNF-a, IL-4, and IL-10 (18,34). In a healthy ex vivo context, we confirm an increased production of these cytokines after Vd2 cell expansion in response to HMBPP and further demonstrate the production of IL-6, IL-9, IL-15, and IL-17.…”

Engagement of NKp30 on Vδ1 T cells induces the production of CCL3, CCL4, and CCL5 and suppresses HIV-1 replication

“…on May 10, 2018. by guest www.bloodjournal.org From pathologic translocation of microflora in the lamina propria and mesenteric lymph nodes after the massive depletion of mucosal CD4 ϩ T cells in acute and highly viremic stages of HIV-1 infection. 24 Importantly, and in line with what was recently demonstrated for V␥9V␦2 T cells in SIV-infected primates, 25 the establishment of novel protocols either inducing NKp30 expression on expanded V␦1 T cells in vivo or adoptively transferring in vitro differentiated NKp30 ϩ V␦1 T cells may be of great therapeutic value in the cure of HIV/AIDS.…”

Mechanisms underlying γδ T-cell subset perturbations in SIV-infected Asian rhesus macaques

“…[16][17][18][19] However, while the biological consequences of these perturbations remain unclear, therapeutic interventions aimed at expanding the V␦2 T-cell subset have resulted in enhanced neutralizing antibody titers in chronically SHIV-infected RMs. 20 The mechanism leading to enhanced V␦2 T cell cytokine production and elevated neutralizing antibody titers in this study was largely unknown.A better understanding of the mechanisms that underlie alterations in ␥␦ T-cell subsets is crucial for future therapeutic interventions aimed at modulating ␥␦ T cells. Chronic immune activation is closely associated with disease progression in HIV/SIV infection, and microbial translocation is well described as one cause of immune activation.…”