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

Abstract

Introduction␥␦ T cells are a minor group of T lymphocytes and are distinct from ␣␤ T cells. 1,2 In humans and nonhuman primates, ␥␦ T cells are composed of 2 predominant subsets based on the differential expression of V␦1 and V␦2 genes. Although the antigen specificity and recognition properties of these 2 subsets have yet to be fully elucidated, 3 ␥␦ T cells can expand during bacterial infections. 4 Indeed, V␦1 T cells can recognize small lipoprotein antigens produced by bacterial pathogens, 5 and V␦2 T cells can respond to several distinct chemical structures such as alkylamines 4 and small phosphoantigens, 6 some of which can be produced either as a byproduct of the microbial nonmevalonate pathway or by altered metabolic pathways in stressed host cells during pathogenic infections. 7 In general, ␥␦ T cells represent approximately 4% of peripheral blood T cells, and the majority of these express the V␦2 gene. 4 However, in the gastrointestinal tract, V␦1 T cells are present at higher frequencies and can comprise up to 40% of intraepithelial lymphocytes. 8 Functionally, ␥␦ T cells are similar to ␣␤ T cells in that they can produce interleukin 17 (IL17), interferon ␥ (IFN␥), and other soluble factors after stimulation through the T-cell receptor (TCR). 9,10 Moreover, ␥␦ T cells have been shown to be critical for the recruitment of neutrophils during bacterial infections. 11 The V␦1 subset also contributes to maintenance of the epidermis and the gastrointestinal (GI) epithelium through the production of keratinocyte and epithelial growth factors. [12][13][14] Alterations of ␥␦ T-cell subsets occur during progressive HIV infection and pathogenic Simian immunodeficiency virus (SIV) infections of rhesus macaques (RMs). [15][16][17][18] Specifically, the V␦1 subset, which is usually localized to the mucosal tissues but not the periphery, becomes prevalent in the peripheral blood relative to the V␦2 subset. 15,16 The mechanisms by which this peripheral V␦1/V␦2 T-cell inversion develops are not well understood, although it has been suggested that preferential loss of V␦2 T cells, thymic dysfunction, and/or V␦1 T-cell expansion may be responsible. [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. 21,22 As ␥␦ T cells seem to be important in the early stages of innate responses to invading microbes, and V␦1 T cells play an important role in g...

Loss of Circulating Mucosal-Associated Invariant T Cells in Common Variable Immunodeficiency Is Associated with Immune Activation and Loss of Eomes and PLZF

“…Overall, this suggests that the loss of MAIT cells in CVID and other diseases could reflect the infection burden. Microbial translocation is now recognized as a driver of immune activation in HIV infection (49) and is associated with an abnormal distribution of d1 and d2 gd T cells in SIV infection (50). We have recently reported that similar perturbations in gd T cells also occur in CVID (32), and in the current study we observed a trend toward an association between the levels of sCD14, an indirect marker of microbial translocation, and MAIT cell loss in CVID.…”

Fc Receptor-Mediated Immune Responses: New Tools But Increased Complexity in HIV Prevention

“…Importantly, while γδT cells make up a small percentage of peripheral blood T cells, they are present at high frequencies in the gut [110], where they could potentially play a major role in protection against HIV/SIV. Here we will limit our discussion to their antibody interactions, which represent a small fraction of their overall impact on the immune system.…”

Mucosal and Systemic γδ+ T Cells Associated with Control of Simian Immunodeficiency Virus Infection

“…In contrast, Vγ9Vδ2 T cells, the Vδ2 subset, are mainly found in peripheral blood and are activated by non-peptidic molecules, such as phosphoantigens, produced by many microbial pathogens and stressed cells (5, 6). Activated γδ T cells exhibit a multiplicity of effector functions including direct killing of infected cells, antibody dependent cellular cytotoxicity (ADCC), and production of cytokines such as IFN-γ (7) and IL17 (8, 9). γδ T cells have antigen presenting and regulatory functions and through cross-talk enhance the cytotoxic effector function of NK cells (10).…”