Human γδ T cell Recognition of lipid A is predominately presented by CD1b or CD1c on dendritic cells

<p>Abstract</p> <p>Background</p> <p>The γδ T cells serve as early immune defense against certain encountered microbes. Only a few γδ T cell-recognized ligands from microbial antigens have been identified so far and the mechanisms by which γδ T cells recognize these ligands remain unknown. Here we explored the mechanism of interaction of human γδ T cells in peripheral blood with Lipid A (LA).</p> <p>Results</p> <p>First, resting γδ T cells (mainly Vδ2 T cells) displayed a strong proliferative response to LA-pulsed monocyte-derived dendritic cells (moDC) and LA-pulsed paraformaldehyde-fixed moDC, but not to free LA in a TCR γδ-dependent manner. Second, anti-CD1b or anti-CD1c antibodies could block proliferative response of resting γδ T cells to LA-loaded moDC. Besides, only LA-loaded CD1b/CD1c-transfected C1R lymphoblastoma cells (CD1b-/CD1c-C1R) were able to stimulate the proliferation of human γδ T cells. Third, the expressions of both Toll-like receptor (TLR)2 and TLR4 on surface of LA-activated γδ T cells were upregulated, whereas only anti-TLR4 antibody could partially block their response to LA; Finally LA-loaded moDCs induce γδ T cells to produce Th1 cytokines, such as IFN-γ.</p> <p>Conclusion</p> <p>Taken together, we found a novel mechanism that human γδ T cells recognize LA in a CD1b- or CD1c-restricted manner in first response against Gram-bacteria, while the interaction between TLR4 on γδ T cells and LA might strengthen the subsequent response of γδ T cells.</p> <p>Reviewers</p> <p>This article was reviewed by Hao Shen, Youwen He (nominated by Dr. Laurence C Eisenlohr), Dr. Michael Lenardo and Dr. Pushpa Pandiyan.</p

γδ T Cells Provide Protective Function in Highly Pathogenic Avian H5N1 Influenza A Virus Infection

Given the high mortality rate (&gt;50%) and potential danger of intrapersonal transmission, highly pathogenic avian influenza (HPAI) H5N1 epidemics still pose a significant threat to humans. γδ T cells, which participate on the front line of the host immune defense, demonstrate both innate, and adaptive characteristics in their immune response and have potent antiviral activity against various viruses. However, the roles of γδ T cells in HPAI H5N1 viral infection remain unclear. In this study, we found that γδ T cells provided a crucial protective function in the defense against HPAI H5N1 viral infection. HPAI H5N1 viruses could directly activate γδ T cells, leading to enhanced CD69 expression and IFN-γ secretion. Importantly, we found that the trimer but not the monomer of HPAI H5N1 virus hemagglutinin (HA) proteins could directly activate γδ T cells. HA-induced γδ T cell activation was dependent on both sialic acid receptors and HA glycosylation, and this activation could be inhibited by the phosphatase calcineurin inhibitor cyclosporin A but not by the phosphatidylinositol 3-kinase (PI3-K) inhibitors wortmannin and LY294002. Our findings provide a further understanding the mechanism underlying γδ T cell-mediated innate and adoptive immune responses against HPAI H5N1 viral infection, which helps to develop novel therapeutic strategies for the treatment of H5N1 infection in the future

A Novel Strategy to Screen Bacillus Calmette-Guérin Protein Antigen Recognized by γδ TCR

BACKGROUND: Phosphoantigen was originally identified as the main γδ TCR-recognized antigen that could activate γδ T cells to promote immune protection against mycobacterial infection. However, new evidence shows that the γδ T cells activated by phosphoantigen can only provide partial immune protection against mycobacterial infection. In contrast, whole lysates of Mycobacterium could activate immune protection more potently, implying that other γδ TCR-recognized antigens that elicit protective immune responses. To date, only a few distinct mycobacterial antigens recognized by the γδ TCR have been characterized. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we established a new approach to screen epitopes or protein antigens recognized by the γδ TCR using Bacillus Calmette-Guérin- (BCG-) specific γ TCR transfected cells as probes to pan a 12-mer random-peptide phage-displayed library. Through binding assays and functional analysis, we identified a peptide (BP3) that not only binds to the BCG-specific γδ TCR but also effectively activates γδ T cells isolated from human subjects inoculated with BCG. Importantly, the γδ T cells activated by peptide BP3 had a cytotoxic effect on THP-1 cells infected with BCG. Moreover, the oxidative stress response regulatory protein (OXYS), a BCG protein that matches perfectly with peptide BP3 according to bioinformatics analysis, was confirmed as a ligand for the γδ TCR and was found to activate γδ T cells from human subjects inoculated with BCG. CONCLUSIONS/SIGNIFICANCE: In conclusion, our study provides a novel strategy to identify epitopes or protein antigens for the γδ TCR, and provides a potential means to screen mycobacterial vaccines or candidates for adjuvant

TCR γ4δ1-Engineered αβT Cells Exhibit Effective Antitumor Activity

Abstract T cell engineering with T cell receptors (TCRs) specific for tumors plays an important role in adoptive T cell transfer (ATC) therapy for cancer. Here, we present a novel strategy to redirect peripheral blood-derived αβT cells against tumors via TCRγ4δ1 gene transduction. The broad-spectrum antitumor activity of TCRδ1 cells in innate immunity is dependent on CDR3δ1. TCRγ4δ1-engineered αβT cells were prepared by lentiviral transduction and characterized by analyzing in vitro and in vivo cytotoxicity to tumors, ability of proliferation and cytokine production, and potential role in autoimmunity. Results show that TCRγ4δ1 genes were transduced to approximately 36% of polyclonal αβT cells. TCRγ4δ1-engineered αβT cells exhibited effective in vitro TCRγδ-dependent cytotoxicity against various tumor cells via the perforin-granzyme pathway. They also showed a strong proliferative capacity and robust cytokine production. TCRγ4δ1-engineered αβT cells neither expressed mixed TCR dimers nor bound/killed normal cells in vitro. More important, adoptive transfer of TCRγ4δ1-engineered αβT cells into nude mice bearing a human HepG2 cell line significantly suppressed tumor growth. Our results demonstrate a novel role for TCRγ4δ1 in gene therapy and ATC for cancer

Human γδ T Cells Augment Antigen Presentation in Listeria Monocytogenes Infection

Abstract Circulating γδ T cells In healthy Individuals rapidly respond to bacterial and viral pathogens. Many studies have demonstrated that γδ T cells are activated and expanded by Listeria monocytogenes (L. monocytogenes), a foodborne bacterial pathogen with high fatality rates. However, the roles of γδ T cells during L. monocytogenes infection are not clear. In the present study, we characterized the morphological characteristics of phagocytosis in γδ T cells after L. monocytogenes infection using transmission electron microscopy. Results show activation markers including human leucocyte antigen DR (HLA-DR) and lymph node-homing receptor CCR7 on γδ T cells were upregulated after stimulation via L. monocytogenes. Significant proliferation and differentiation of primary αβ T cells was also observed after coculture of peripheral blood mononuclear cells with γδ T cells anteriorly stimulated by L. monocytogenes. L. monocytogenes infection decreased the percentage of γδ T cells in mouse intraepithelial lymphocytes (IELs) and increased MHC-II expression on the surface of γδ T cells in vivo. Our findings shed light on antigen presentation of γδ T cells during L. monocytogenes infection

γδ T cells are involved in acute HIV infection and associated with AIDS progression.

BACKGROUND: Early diagnosis is vital to HIV control. γδ T cells play critical roles in viral infections, but their activation in acute HIV infected patients and follow up to 18 months has not been described. METHODS: Changes in γδ T cells, including subsets, function and activation, in treated and untreated acutely HIV-infected patients (n = 79) were compared by cytotoxicity assay and flow cytometry with healthy controls (n = 21) at month 0, 6, 12 and 18. RESULTS: In acutely HIV-infected patients, Vδ1 cell proportion was elevated (P = 0.027) with Vδ2 population reduced (P = 0.002). Effector and central memory γδ T cell factions were decreased (P = 0.006 and P = 0.001, respectively), while proportion of terminal γδ T cells increased (P = 0.002). γδ T cell cytotoxicity was compromised over time. Fraction of IL-17-producing cells increased (P = 0.008), and IFN-γ-producing cells were unaffected (P = 0.115). Elevation of a microbial translocation marker, sCD14, was associated with γδ T cell activation (P = 0.001), which increased in a time-dependent manner, correlating with CD4/CD8 T cell activation set-points and CD4 counts. Antiretroviral therapy did not affect these changes. CONCLUSIONS: γδ T cell subpopulation and functions change significantly in acute HIV infection and over time. Early γδ T cell activation was associated with CD4/CD8 T cell activation set-points, which predict AIDS progression. Therefore, γδ T cell activation represents a potential surrogate marker of AIDS progression