Abstract
Human γδ T cells expressing the Vδ1 T cell receptor (TCR) recognize self and microbial antigens and stress-inducible molecules in a major histocompatibility complex-unrestricted manner and are an important source of innate interleukin (IL)-17. Vδ1 T cells are expanded in the circulation and intestines of patients with human immunodeficiency virus (HIV) infection. In this study, we show that patients with HIV have elevated frequencies, but not absolute numbers, of circulating Vδ1 T cells compared to control subjects. This increase was most striking in the patients with Candida albicans co-infection. Using flow cytometry and confocal microscopy, we identify two populations of Vδ1 T cells, based on low and high expression of the ε chain of the CD3 protein complex responsible for transducing TCR-mediated signals (denoted CD3εlo and CD3εhi Vδ1 T cells). Both Vδ1 T cell populations expressed the CD3 ζ-chain, also used for TCR signaling. Using lines of Vδ1 T cells generated from healthy donors, we show that CD3ε can be transiently downregulated by activation but that its expression is restored over time in culture in the presence of exogenous IL-2. Compared to CD3εhi Vδ1 T cells, CD3εlo Vδ1 T cells more frequently expressed terminally differentiated phenotypes and the negative regulator of T cell activation, programmed death-1 (PD-1), but not lymphocyte-activation gene 3, and upon stimulation in vitro, only the CD3εhi subset of Vδ1 T cells, produced IL-17. Thus, while HIV can infect and kill IL-17-producing CD4+ T cells, Vδ1 T cells are another source of IL-17, but many of them exist in a state of exhaustion, mediated either by the induction of PD-1 or by downregulation of CD3ε expression.
Highlights
T cells expressing the γδ T cell receptor (TCR) represent a minor population of lymphocytes that expands in blood and peripheral tissues upon exposure to bacteria [1, 2], fungi [3], yeast [4, 5], and viruses [6,7,8]. γδ TCRs bind non-peptide antigens in a major histocompatibility complex (MHC) unrestricted manner, leading to phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAM) on the CD3 γ, δ, ε, ζ, and sometimes FcRγ proteins [9, 10]
Peripheral blood mononuclear cells were prepared from blood samples of 36 patients with human immunodeficiency virus (HIV) infection and 23 healthy donors, stained with monoclonal antibody (mAb) specific for CD3ε and the Vδ1 TCR and analyzed by flow cytometry (Figure 1A)
We investigated if CD3εlo and CD3εhi Vδ1 T cells from patients with HIV infection and control subjects differ in their ability to produce IL-17. γδ T cell-enriched Peripheral blood mononuclear cells (PBMCs) from 13 healthy donors and 11 patients with HIV were stimulated for 6 h with phorbol myristate acetate with ionomycin (PMA/I) or incubated in medium alone and IL-17A expression by gated CD3εlo and CD3εhi Vδ1 T cells was examined by flow cytometry (Figure 8A)
Summary
T cells expressing the γδ T cell receptor (TCR) represent a minor population of lymphocytes that expands in blood and peripheral tissues upon exposure to bacteria [1, 2], fungi [3], yeast [4, 5], and viruses [6,7,8]. γδ TCRs bind non-peptide antigens in a major histocompatibility complex (MHC) unrestricted manner, leading to phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAM) on the CD3 γ, δ, ε, ζ, and sometimes FcRγ proteins [9, 10]. Γδ TCRs bind non-peptide antigens in a major histocompatibility complex (MHC) unrestricted manner, leading to phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAM) on the CD3 γ, δ, ε, ζ, and sometimes FcRγ proteins [9, 10]. They respond rapidly by killing target cells, releasing cytokines, and providing ligands that mediate the activation and differentiation of other cells of the immune system [11, 12, 13]. Vδ1 T cells proliferate, release cytokines, such as interferon-γ (IFN-γ), tumor necrosis factor-α, and interleukin-17 (IL-17), chemokines, such as CCL3, CCL4, and CCL5, and they can kill CD4+ T cells in vitro [4, 21, 23, 25,26,27]
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