Vδ2 T-cell Research Articles

Costimulation of γδTCR and TLR7/8 promotes Vδ2 T-cell antitumor activity by modulating mTOR pathway and APC function

BackgroundGamma delta (γδ) T cells are attractive effector cells for cancer immunotherapy. Vδ2 T cells expanded by zoledronic acid (ZOL) are the most commonly used γδ T cells for adoptive...

Imperfect storm: is interleukin-33 the Achilles heel of COVID-19?

The unique cytokine signature of COVID-19 might provide clues to disease mechanisms and possible future therapies. Here, we propose a pathogenic model in which the alarmin cytokine, interleukin (IL)-33, is a key player in driving all stages of COVID-19 disease (ie, asymptomatic, mild–moderate, severe–critical, and chronic–fibrotic). In susceptible individuals, IL-33 release by damaged lower respiratory cells might induce dysregulated GATA-binding factor 3-expressing regulatory T cells, thereby breaking immune tolerance and eliciting severe acute respiratory syndrome coronavirus 2-induced autoinflammatory lung disease. Such disease might be initially sustained by IL-33-differentiated type-2 innate lymphoid cells and locally expanded γδ T cells. In severe COVID-19 cases, the IL-33–ST2 axis might act to expand the number of pathogenic granulocyte–macrophage colony-stimulating factor-expressing T cells, dampen antiviral interferon responses, elicit hyperinflammation, and favour thromboses. In patients who survive severe COVID-19, IL-33 might drive pulmonary fibrosis by inducing myofibroblasts and epithelial–mesenchymal transition. We discuss the therapeutic implications of these hypothetical pathways, including use of therapies that target IL-33 (eg, anti-ST2), T helper 17-like γδ T cells, immune cell homing, and cytokine balance.

Exosomes derived from Vδ2-T cells control Epstein-Barr virus-associated tumors and induce T cell antitumor immunity.

Treatment of life-threatening Epstein-Barr virus (EBV)-associated tumors remains a great challenge, especially for patients with relapsed or refractory disease. Here, we found that exosomes derived from phosphoantigen-expanded Vδ2-T cells (Vδ2-T-Exos) contained death-inducing ligands (FasL and TRAIL), an activating receptor for natural killer (NK) cells (NKG2D), immunostimulatory ligands (CD80 and CD86), and antigen-presenting molecules (MHC class I and II). Vδ2-T-Exos targeted and efficiently killed EBV-associated tumor cells through FasL and TRAIL pathways and promoted EBV antigen-specific CD4 and CD8 T cell expansion. Administration of Vδ2-T-Exos effectively controlled EBV-associated tumors in Rag2-/-γc-/- and humanized mice. Because expanding Vδ2-T cells and preparing autologous Vδ2-T-Exos from cancer patients ex vivo in large scale is challenging, we explored the antitumor activity of allogeneic Vδ2-T-Exos in humanized mouse cancer models. Here, we found that allogeneic Vδ2-T-Exos had more effective antitumor activity than autologous Vδ2-T-Exos in humanized mice; the allogeneic Vδ2-T-Exos increased the infiltration of T cells into tumor tissues and induced more robust CD4 and CD8 T cell-mediated antitumor immunity. Compared with exosomes derived from NK cells (NK-Exos) with direct cytotoxic antitumor activity or dendritic cells (DC-Exos) that induced T cell antitumor responses, Vδ2-T-Exos directly killed tumor cells and induced T cell-mediated antitumor response, thus resulting in more effective control of EBV-associated tumors. This study provided proof of concept for the strategy of using Vδ2-T-Exos, especially allogeneic Vδ2-T-Exos, to treat EBV-associated tumors.

Identification of a regulatory Vδ1 gamma delta T cell subpopulation expressing CD73 in human breast cancer.

γδ T cells contribute to the immune response against many cancers, notably through their powerful effector functions that lead to the elimination of tumor cells and the recruitment of other immune cells. However, their presence in the tumor microenvironment has been associated with poor prognosis in breast, colon, and pancreatic cancer, suggesting that γδ T cells may also display pro-tumor activities. Here, we identified in blood from healthy donors a subpopulation of Vδ1T cells that represents around 20% of the whole Vδ1 population, expresses CD73, and displays immunosuppressive phenotype and functions (i.e., production of immunosuppressive molecules, such as IL-10, adenosine, and the chemotactic factor IL-8, and inhibition of αβT cell proliferation). We then found that in human breast tumors, γδ T cells were present particularly in late stage breast cancer samples, and that ∼20% of tumor-infiltrating γδ T cells expressed CD73. Taken together, these results suggest that regulatory γδ T cells are present in the breast cancer microenvironment and may display immunosuppressive functions through the production of immunosuppressive molecules, such as IL-10, IL-8, and adenosine, thus promoting tumor growth.

Analysis of colon-infiltrating γδ Tcells in chronic inflammatory bowel disease and in colitis-associated cancer.

Inflammatory bowel disease (IBD) remains a global health problem with a significant percentage of patients progressing to chronic inflammation and colitis-associated cancer (CAC). Whether or not γδ Tcells contribute to initiation and maintenance of inflammation in IBD and in the development of CAC is not known. We have evaluated the frequency, phenotype, and functions of γδ Tcells among tissue-infiltrating lymphocytes in healthy donors and IBD and CAC patients. Results show that Vδ1 Tcells are the dominant γδ T-cell population in healthy tissue, whereas Vδ2 T significantly abound in chronic IBD. Vδ2 Tcells produce more IFN-γ, TNF-α, and IL-17 than Vδ1 Tcells in chronic inflamed IBD. In CAC patients no significant cytokine production was detected in tissue-resident Vδ1 Tcells, but Vδ2 Tcells produced remarkable amounts of IFN-γ and TNF-α; these data were confirmed by the analysis of an independent cohort of IBD transcriptomes. Moreover, transcriptomes of IBD patients revealed a clear-cut clusterization of genes related with the maintenance of the inflammatory status. In conclusion, our results demonstrating that Vδ2 Tcells have a proinflammatory profile in chronic IBD are suggestive of their participation in IBD and CAC pathogenesis.

Vδ2 T-Cells Kill ZIKV-Infected Cells by NKG2D-Mediated Cytotoxicity

An expansion of effector/activated Vδ2 T-cells was recently described in acute Zika virus (ZIKV)-infected patients, but their role in the protective immune response was not clarified. The aim of this study was to define the antiviral activity of Vδ2 T-cells against ZIKV-infected cells. The Vδ2 T-cells expansion and their cytotoxic activity against ZIKV-infected cells were tested in vitro and analyzed by RT-PCR and flow cytometry. We found that ZIKV infection was able to induce Vδ2 T-cells expansion and sensitized A549 cells to Vδ2-mediated killing. Indeed, expanded Vδ2 T-cells killed ZIKV-infected cells through degranulation and perforin release. Moreover, ZIKV infection was able to increase the expression on A549 cells of NKG2D ligands (NKG2DLs), namely MICA, MICB, and ULBP2, at both the mRNA and protein levels, suggesting the possible involvement of these molecules in the recognition by NKG2D-expressing Vδ2 T-cells. Indeed, the killing of ZIKV-infected cells by expanded Vδ2 T-cells was mediated by NKG2D/NKG2DL interaction as NKG2D neutralization abrogated Vδ2 cytotoxicity. Our data showed a strong antiviral activity of Vδ2 T-cells against ZIKV-infected cells, suggesting their involvement in the protective immune response. Other studies are necessary to investigate whether the lack of Vδ2 T-cells expansion in vivo may be associated with disease complications.

Persistent gamma delta T-cell dysfunction in chronic HCV infection despite direct-acting antiviral therapy induced cure.

Immune dysfunction is a hallmark of chronic HCV infection and viral clearance with direct antivirals recover some of these immune defects. TCRVγ9Vδ2 T-cell dysfunction in treated HCV patients however is not well studied and was the subject of this investigation. Peripheral blood cells from patients who had achieved sustained virologic response (SVR) or those who had relapsed after interferon-free therapy were phenotyped using flow cytometry. Functional potential of Vγ9Vδ2 T cells was tested by measuring proliferation in response to aminobisphosphonate zoledronic acid, and cytotoxicity against HepG2 hepatoma cell line. TCR sequencing was performed to analyse impact of HCV infection on Vδ2 T-cell repertoire. Vγ9Vδ2 cells from patients were activated and therapy resulted in reduction of CD38 expression on these cells in SVR group. Relapsed patients had Vδ2 cells with persistently activated and terminally differentiated cytotoxic phenotype (CD38+ CD45RA+ CD27- CD107a+ ). Irrespective of outcome with therapy, majority of patients had persistently poor Vδ2 T-cell proliferative response to zoledronate along with lower expression of CD56, which identifies anti-tumour cytotoxic subset, relative to healthy controls. There was no association between the number of antigen reactive Vγ2-Jγ1.2 TCR rearrangements at baseline and levels of proliferation indicating nonresponse to zoledronate is not due to depletion of phosphoantigen responding chains. Thus, HCV infection results in circulating Vγ9Vδ2 T cells with a phenotype equipped for immediate effector function but poor cytokine response and expansion in response to antigen, a functional defect that may have implications for susceptibility for carcinogenesis despite HCV cure.

Changes and clinical significance of γδT cells in peripheral blood of patients with chronic hepatitis B during pegylated interferon α-2a treatment

Objective: To observe the changes of γδT cells in the peripheral blood of patients with chronic hepatitis B (CHB) during pegylated interferon α-2a treatment, and to analyze the correlation between clinical indicators and curative effects. Methods: Peripheral blood of hepatitis B e antigen (HBeAg)-positive CHB patients were collected at different time points of Peg-IFNα-2a treatment, including 17 patients at 0 weeks, 20 patients at 12 weeks, 20 patients at 24 weeks, and 16 patients at 48 weeks. From these 11 patients, blood samples were frequently observed at 0, 12, 24, and 48 weeks of treatment. The frequencies of γδT and its subpopulation cells Vδ1T, Vδ2T, effector memory γδT (γδTem), central memory γδT (γδTcm), initial γδT (γδTnaive) and terminal differentiation effect γδT (γδTeff) cells in peripheral blood were detected by flow cytometry. Liver function, serum HBV markers and HBV DNA levels were measured simultaneously. SPSS 23.0 statistical software was used to analyze the differences in cell proportions at each treatment time point, and the correlation between cell proportions and alanine aminotransferase (ALT), HBsAg, HBeAg or HBV DNA levels. In addition, the correlation between the proportions of γδT and its subpopulation cells and the response to Peg-IFNα-2a treatment in the 11 patients with continuous follow-up were analyzed. Results: The percentage of γδT and Vδ2T cells in peripheral blood of patients with CHB decreased gradually during the period of 0-48 weeks of Peg-IFNα-2a treatment. The percentages of γδT cells and Vδ2T cells at 48 weeks were 6.89% (5%, 8.15%), 4.61% (2.16%, 6.50%), respectively; significantly lower than the 0 week [12.5% ​​(7.73%, 19%), 6.59% (3.86%, 13.62%)], the differences were statistically significant (P < 0.05). The proportions of Vδ1T, γδTem, γδTcm, γδTnaive, or γδTeff subpopulations were not statistically different at each time points (all P > 0.05). At the same time, the levels of ALT, HBsAg, HBeAg or HBV DNA were positively correlated with the ratio of γδT or Vδ2T cells (P < 0.05). Among the 11 patients with continuous followed- up, the proportion of γδTem cells in responders was significantly lower than that of non-responders at each time points, and the difference was statistically significant (P < 0.05). There was no statistically significant difference between the two groups (all P > 0.05). Conclusion: The proportion of γδT cells in the course of CHB treatment with Peg-IFNα-2a reduces the liver inflammation by decreasing the replication of HBV virus. Chronic hepatitis B patients with a lower proportion of effector memory (γδTem) cells may be more likely to get better response with Peg-IFNα-2a.

γδ T Cells in Peripheral Blood of Glioma Patients.

BackgroundGlioma is a common brain malignancy, but the effects of the γδ T cells and their subsets in peripheral blood in patients with glioma have not been reported.Material/MethodsFlow cytometry was used to analyze the functions and expressions of δ T cells and their subsets in peripheral blood in healthy controls and patients with glioma. The Vδ2 T cells and the activation of killing function-related signaling pathway were analyzed by Western blot assay; the immunosuppressive functions of Vδ1 T cells were detected by CFSE proliferation assay; and the Vδ2 T cell killing functions were detected by killing assay.ResultsCompared with the healthy controls, the ratio of Vδ1 T cells was significantly increased and the ratio of Vδ2 T cells was significantly decreased. After in vitro culture and anti-TCR γδ antibody stimulation and in the presence of IL-2, in the patients with glioma, the Vδ1 T cells dominated and Vδ2 T cells were scarce. Flow cytometry staining showed that expression of immunosuppression-related molecules on the Vδ1 T cell surface was significantly increased, while the expression of killing function-related molecules and the activation of killing function-related signaling pathway in the Vδ2 T cells were significantly decreased. Functional test results showed that the immunosuppressive function of Vδ1T cells was enhanced and the killing function of Vδ1T cells was reduced.ConclusionsThe ratio and function changes of Vδ1 T cells and Vδ2 T cells are possibly associated with the pathogenesis of glioma.

Unconventional T cells in chronic hepatitis B patients on long-term suppressive therapy with tenofovir followed by a Peg-IFN add-on strategy: A randomized study.

HBV eradication in chronic hepatitis B (CHB) subjects is rarely achieved with either nucleos(t)ide analogues (NA) or pegylated interferon (Peg-IFN), which both have a limited effect in restoring immune responses. Thirty CHB subjects on long-term treatment with tenofovir (TDF) and HBV suppression were enrolled and randomized 1:2 to either receive Peg-IFN-α-2a add-on therapy or continue TDF alone. We studied γδ T and iNKT frequency and function (by flow cytometry) at baseline, at 12weeks and 12weeks after the end of treatment. A higher reduction in qHBsAg occurred in the add-on group compared with the NA group at W12 (P=.016) and at W24 (P=.012). A decline of qHBsAg ≥0.5 log10 at week 24 occurred in 4 of 10 patients in the add-on arm and 1 of 20 in the NA arm, respectively (P=.03). HBsAg loss was seen in 20% of subjects in the add-on group and in none of the NA group. Compared to HBV negative, CHB on TDF showed lower frequency of iNKT (P=.03) and γδ T cells (P=.03) as well as fewer γδ T cells expressing Vδ2 T-cell receptors (P=.005). No changes in unconventional T-cell frequency and function were shown in both add-on and NA patients nor were differences detected between the two treatment groups. We report persistent impairment of unconventional T cells in CHB. Despite a greater qHBsAg decline of add-on patients, our data failed to detect any effect of Peg-IFN treatment on unconventional T cells.

Chemotaxis of Vδ2 T cells to the joints contributes to the pathogenesis of rheumatoid arthritis

ObjectivesTo explore the role of Vδ2 T cells in the pathogenesis of rheumatoid arthritis (RA).MethodsSixty-eight patients with RA, 21 patients with osteoarthritis and 21 healthy controls were enrolled in the...

Clonal expansion shapes the human Vδ1T cell receptor repertoire.

Clonal expansion shapes the human Vδ1T cell receptor repertoire.

The role of γδ-T cells during human pregnancy.

Pregnancy is an evolutionarily important and mysterious process. The placenta, as the nutrient and gas exchange organ, plays an essential role during this process. In addition, the interaction between trophoblast and maternal immune cells at the maternal-fetal interface is also associated with successful pregnancy. Human leukocyte antigen (HLA) molecules on trophoblast cells are involved in protecting the fetus from maternal rejection. Trophoblast cells comprise three subpopulations, including syncytiotrophoblast cells, cytotrophoblast cells, and extravillous trophoblast cells, and these cells express different HLA molecules. Syncytiotrophoblast and extravillous trophoblast cells encounter maternal immune cells from different sources, such as blood or decidua. The increased γδ-T cells during human normal pregnancy indicate that these cells may play a role in this process. In peripheral blood, Vγ9Vδ2-T cells display cytotoxicity through the recognition of phosphoantigens derived from pathogens. However, HLA-E molecules protect the trophoblast cells from the cytotoxicity of Vγ9Vδ2-T cells through binding to the inhibitory receptor, CD94/NKG2A. In decidua, the main Vδ1-T cells maintain the pregnancy through the secretion of cytokines. In addition, the imbalance between Vγ9Vδ2-T and Vδ1-T cells, and the abnormal expression of the receptors on γδ-T cells were observed in adverse pregnancy.

Different features of Vδ2 T and NK cells in fatal and non-fatal human Ebola infections.

BackgroundHuman Ebola infection is characterized by a paralysis of the immune system. A signature of αβ T cells in fatal Ebola infection has been recently proposed, while the involvement of innate immune cells in the protection/pathogenesis of Ebola infection is unknown. Aim of this study was to analyze γδ T and NK cells in patients from the Ebola outbreak of 2014–2015 occurred in West Africa, and to assess their association with the clinical outcome.Methodology/Principal findingsNineteen Ebola-infected patients were enrolled at the time of admission to the Ebola Treatment Centre in Guinea. Patients were divided in two groups on the basis of the clinical outcome. The analysis was performed by using multiparametric flow cytometry established by the European Mobile Laboratory in the field. A low frequency of Vδ2 T-cells was observed during Ebola infection, independently from the clinical outcome. Moreover, Vδ2 T-cells from Ebola patients massively expressed CD95 apoptotic marker, suggesting the involvement of apoptotic mechanisms in Vδ2 T-cell loss. Interestingly, Vδ2 T-cells from survivors expressed an effector phenotype and presented a lower expression of the CTLA-4 exhaustion marker than fatalities, suggesting a role of effector Vδ2 T-cells in the protection. Furthermore, patients with fatal Ebola infection were characterized by a lower NK cell frequency than patients with non fatal infection. In particular, both CD56bright and CD56dim NK frequency were very low both in fatal and non fatal infections, while a higher frequency of CD56neg NK cells was associated to non-fatal infections. Finally, NK activation and expression of NKp46 and CD158a were independent from clinical outcome.Conclusions/SignificancesAltogether, the data suggest that both effector Vδ2 T-cells and NK cells may play a role in the complex network of protective response to EBOV infection. Further studies are required to characterize the protective effector functions of Vδ2 and NK cells.

Heterogeneous yet stable Vδ2(+) T-cell profiles define distinct cytotoxic effector potentials in healthy human individuals

Human γδ T cells display potent responses to pathogens and malignancies. Of particular interest are those expressing a γδ T-cell receptor (TCR) incorporating TCRδ-chain variable-region-2 [Vδ2(+)], which are activated by pathogen-derived phosphoantigens (pAgs), or host-derived pAgs that accumulate in transformed cells or in cells exposed to aminobisphosphonates. Once activated, Vδ2(+) T cells exhibit multiple effector functions that have made them attractive candidates for immunotherapy. Despite this, clinical trials have reported mixed patient responses, highlighting a need for better understanding of Vδ2(+) T-cell biology. Here, we reveal previously unappreciated functional heterogeneity between the Vδ2(+) T-cell compartments of 63 healthy individuals. In this cohort, we identify distinct "Vδ2 profiles" that are stable over time; that do not correlate with age, gender, or history of phosphoantigen activation; and that develop after leaving the thymus. Multiple analyses suggest these Vδ2 profiles consist of variable proportions of two dominant but contrasting Vδ2(+) T-cell subsets that have divergent transcriptional programs and that display mechanistically distinct cytotoxic potentials. Importantly, an individual's Vδ2 profile predicts defined effector capacities, demonstrated by contrasting mechanisms and efficiencies of killing of a range of tumor cell lines. In short, these data support patient stratification to identify individuals with Vδ2 profiles that have effector mechanisms compatible with tumor killing and suggest that tailored Vδ2-profile-specific activation protocols may maximize the chances of future treatment success.

IL-17A-producing CD30(+) Vδ1 T cells drive inflammation-induced cancer progression.

Although it has been suspected that inflammation is associated with increased tumor metastasis, the exact type of immune response required to initiate cancer progression and metastasis remains unknown. In this study, by using an in vivo tumor progression model in which low tumorigenic cancer cells acquire malignant metastatic phenotype after exposure to inflammation, we found that IL‐17A is a critical cue for escalating cancer cell malignancy. We further demonstrated that the length of exposure to an inflammatory microenvironment could be associated with acquiring greater tumorigenicity and that IL‐17A was critical for amplifying such local inflammation, as observed in the production of IL‐1β and neutrophil infiltration following the cross‐talk between cancer and host stromal cells. We further determined that γδT cells expressing Vδ1 semi‐invariant TCR initiate cancer‐promoting inflammation by producing IL‐17A in an MyD88/IL‐23‐dependent manner. Finally, we identified CD30 as a key molecule in the inflammatory function of Vδ1T cells and the blockade of this pathway targeted this cancer immune‐escalation process. Collectively, these results reveal the importance of IL‐17A‐producing CD30+ Vδ1T cells in triggering inflammation and orchestrating a microenvironment leading to cancer progression.

Frequent Malaria Drives Progressive Vδ2 T-Cell Loss, Dysfunction, and CD16 Up-regulation During Early Childhood.

γδ T cells expressing Vδ2 may be instrumental in the control of malaria, because they inhibit the replication of blood-stage parasites in vitro and expand during acute malaria infection. However, Vδ2 T-cell frequencies and function are lower among children with heavy prior malaria exposure. It remains unclear whether malaria itself is driving this loss. Here we measure Vδ2 T-cell frequency, cytokine production, and degranulation longitudinally in Ugandan children enrolled in a malaria chemoprevention trial from 6 to 36 months of age. We observed a progressive attenuation of the Vδ2 response only among children incurring high rates of malaria. Unresponsive Vδ2 T cells were marked by expression of CD16, which was elevated in the setting of high malaria transmission. Moreover, chemoprevention during early childhood prevented the development of dysfunctional Vδ2 T cells. These observations provide insight into the role of Vδ2 T cells in the immune response to chronic malaria.

The Therapeutic Effect of Pamidronate on Lethal Avian Influenza A H7N9 Virus Infected Humanized Mice.

A novel avian influenza virus H7N9 infection occurred among human populations since 2013. Although the lack of sustained human-to-human transmission limited the epidemics caused by H7N9, the late presentation of most patients and the emergence of neuraminidase-resistant strains made the development of novel antiviral strategy against H7N9 in urgent demands. In this study, we evaluated the potential of pamidronate, a pharmacological phosphoantigen that can specifically boost human Vδ2-T-cell, on treating H7N9 virus-infected humanized mice. Our results showed that intraperitoneal injection of pamidronate could potently decrease the morbidity and mortality of H7N9-infected mice through controlling both viral replication and inflammation in affected lungs. More importantly, pamidronate treatment starting from 3 days after infection could still significantly ameliorate the severity of diseases in infected mice and improve their survival chance, whereas orally oseltamivir treatment starting at the same time showed no therapeutic effects. As for the mechanisms underlying pamidronate-based therapy, our in vitro data demonstrated that its antiviral effects were partly mediated by IFN-γ secreted from human Vδ2-T cells. Meanwhile, human Vδ2-T cells could directly kill virus-infected host cells in a perforin-, granzyme B- and CD137-dependent manner. As pamidronate has been used for osteoporosis treatment for more than 20 years, pamidronate-based therapy represents for a safe and readily available option for clinical trials to treat H7N9 infection.

Abstract 1311: The frequency of circulating Vδ1-positive but not Vδ2-positive γ/δ T cells correlates negatively with survival in late-stage melanoma and may be increased by ipilimumab treatment

Abstract Recently, there has been a resurgence of interest in the possibility of using γ/δ-T cells in cancer immunotherapy, because these cells can kill melanoma cells in vitro, and IL-2 and zoledronate treatment can expand some human γδ cells in vitro and in animal models in vivo. The presence of the main subsets of γ/δ-T cells in late-stage melanoma patients and relationship with survival has not been extensively explored, although relatively lower percentages of Vδ2-positive cells has been reported in melanoma. Here, we present preliminary data on associations between the major γ/δ-T cell subsets and survival in melanoma patients, and whether baseline data are informative for predicting responses to ipilimumab treatment. We used a carefully validated set of monoclonal antibodies to assess γ/δ-phenotypes, because we found that certain commercial reagents were not behaving as specified (Wistuba-Hamprecht et al. OMIP-020: phenotypic characterization of human γδ T-cells by multicolor flow cytometry. Cytometry A. 2014; 85:522-4). Comparing a total of 39 stage IV melanoma patients with 27 controls, we found no overall differences in Vδ1 or Vδ2 T-cell frequencies, or in proportions of naïe (CD27, CD28-double positive, CD45RA+)-vs -late-differentiated (CD27,CD28-double negative, CD45RA+) γ/δ cells. However, Kaplan-Meier plots stratifying individual patients into groups with Vδ1 or Vδ2 frequencies above or below the median showed that the presence of Vδ1 but not Vδ2 cells negatively correlated with longer survival (p = 0.033 log-rank; p = 0.047 Breslow). In a subgroup of 9 patients, ipilimumab treatment resulted in an increase of peripheral Vδ1+ T-cells (p = 0.0391, Wilcoxon) but not of Vδ2+ T-cells (p = 0.375, Wilcoxon). We are currently analyzing data from a larger prospective study of ipilimumba treatment with over 100 patients, to confirm or refute these results. Citation Format: Kilian Wistuba-Hamprecht, Benjamin Weide, Alexander Martens, Graham P. Pawelec. The frequency of circulating Vδ1-positive but not Vδ2-positive γ/δ T cells correlates negatively with survival in late-stage melanoma and may be increased by ipilimumab treatment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1311. doi:10.1158/1538-7445.AM2015-1311

Primary and Chronic HIV Infection Differently Modulates Mucosal Vδ1 and Vδ2 T-Cells Differentiation Profile and Effector Functions.

Gut-associated immune system has been identified as a major battlefield during the early phases of HIV infection. γδ T-cells, deeply affected in number and function after HIV infection, are able to act as a first line of defence against invading pathogens by producing antiviral soluble factors and by killing infected cells. Despite the relevant role in mucosal immunity, few data are available on gut-associated γδ T-cells during HIV infection. Aim of this work was to evaluate how primary (P-HIV) and chronic (C-HIV) HIV infection affects differentiation profile and functionality of circulating and gut-associated Vδ1 and Vδ2 T-cells. In particular, circulating and mucosal cells were isolated from respectively whole blood and residual gut samples from HIV-infected subjects with primary and chronic infection and from healthy donors (HD). Differentiation profile and functionality were analyzed by multiparametric flow cytometry. P-HIV and C-HIV were characterized by an increase in the frequency of effector Vδ1-T cells both in circulating and mucosal compartments. Moreover, during P-HIV mucosal Vδ1 T-cells expressed high levels of CD107a, suggesting a good effector cytotoxic capability of these cells in the early phase of infection that was lost in C-HIV. P-HIV induced an increase in circulating effector Vδ2 T-cells in comparison to C-HIV and HD. Notably, P-HIV as well as HD were characterized by the ability of mucosal Vδ2 T-cells to spontaneously produce IFN-γ that was lost in C-HIV. Altogether, our data showed for the first time a functional capability of mucosal Vδ1 and Vδ2 T-cells during P-HIV that was lost in C-HIV, suggesting exhaustion mechanisms induced by persistent stimulation.