Inversion of the Vδ1 to Vδ2 γδ T cell ratio in CVID is not restored by IVIg and is associated with immune activation and exhaustion

Paquin‐Proulx, Dominic; Barsotti, Nathália Silveira; Santos, Bianca A. N.; Marinho, Ana Karolina Barreto Berselli; Kokron, Cristina Maria; Carvalho, Karina I.; Barros, Myrthes Toledo; Kalil, Jorge; Nixon, Douglas F.; Kallas, Esper G.

doi:10.1097/md.0000000000004304

Cited by 14 publications

(17 citation statements)

References 36 publications

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“…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. Two studies have reported elevated levels of LPS in CVID (30,31) and elevated LPS levels were associated with CD4 + T cell exhaustion.…”

Section: Discussionsupporting

confidence: 68%

“…Study cohort and samples CVID patients and healthy controls were enrolled at the Hospital das Clínicas, Medical School, University of São Paulo, and their demographics have been previously described (32), or at the Children's National Medical Center (Washington, DC) ( Table I). The study was approved by the Hospital das Clínicas, University of São Paulo Medical School Ethics Committee, and written informed consent was provided by all participants or their legal guardians in accordance with the Declaration of Helsinki.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2017

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Common variable immunodeficiency (CVID) is characterized by low levels of Igs leading to increased risk of infections. Mucosal-associated invariant T (MAIT) cells are a recently identified population of innate T cells with potent antibacterial activity. We hypothesized that CVID is associated with alterations in MAIT cells. Cryopreserved PBMC from CVID patients and healthy controls were used to study the frequency, phenotype, and response to Escherichia coli stimulation of MAIT cells by flow cytometry. MAIT cell frequency and absolute counts were depressed in CVID. Residual MAIT presented elevated coexpression of CD38 and HLA-DR, and reduced expression of CCR6, whereas levels of CD127 (IL-7 receptor) were unchanged. CVID patients also had an accumulation of MAIT cells lacking the critical transcription factors eomesodermin and promyelocytic leukemia zinc finger protein. MAIT cell frequency was inversely associated with levels of soluble CD14, with coexpression of CD38 and HLA-DR, and accumulation of MAIT cells lacking eomesodermin or promyelocytic leukemia zinc finger protein expression. None of these changes were normalized by IgG replacement therapy. Finally, MAIT cells from CVID patients displayed poor IFN-γ responses to E. coli stimulation, in part due to defective Ag presentation, and these responses were increased by pretreatment with IL-7. Defective MAIT cell response may contribute to the increased incidence of microbial infections seen in CVID patients on IgG replacement therapy.

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Section: Discussionsupporting

confidence: 68%

Section: Methodsmentioning

confidence: 99%

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

et al. 2017

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“…Viallard et al [68] showed that patients with low CD27 + B-cell counts had higher percentages of HLA-DR CD8 T + cells with a differentiated effector phenotype, thus further confirming a higher activation status of CD8 + cells in CVID patients [69]. Finally, Paquin-Proulx et al [70] found a specific subset of γδ T cells expanded in CVID patients. Although they suggested that this deviation in γδ T-cell subsets is a general feature of CVID patients, further studies are needed to confirm this observation.…”

Section: T-cell Subsetsmentioning

confidence: 91%

Common Variable Immunodeficiency: Epidemiology, Pathogenesis, Clinical Manifestations, Diagnosis, Classification, and Management

Yazdani¹,

Habibi²,

Sharifi³

et al. 2020

J Investig Allergol Clin Immunol

111

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Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by hypogammaglobulinemia and increased susceptibility to recurrent bacterial infections. It is the most frequent symptomatic antibody deficiency, with a wide variety of infectious and noninfectious complications. Numerous studies have demonstrated that immunological and genetic defects are involved in the pathogenesis of CVID. However, in most cases, the genetic background of the disease remains unidentified. This review aims to discuss various aspects of CVID, including epidemiology, pathogenesis, symptoms, diagnosis, classification, and management.

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“…An early in vitro study addressed the expression profile and functionality of PD-1/PD-L1 in γδ T-cells following stimulation with HMBPP and suggested that the PD-1/PD-L1 axis is important for regulation of anti-tumor mechanisms of γδ T-cells ( 196 ). Later it was found that PD-1 expression is more frequent on Vδ1, compared with Vδ2 T-cells ( 197 ) and equably distributed over several functionally distinctive subsets of Vγ9Vδ2 T-cells ( 44 ). A report that ex vivo cultivated Vδ2 T-cells depict stable, low cell surface expression of PD-1 following adoptive transfer ( 198 ) might fit the observations that PD-1 is only temporarily upregulated following in vitro stimulation as it has been reported both for HMBPP and ZOL ( 196 , 198 ).…”

Section: Targeting Activating and Inhibitory Receptorsmentioning

confidence: 99%

Improving the Efficiency of Vγ9Vδ2 T-Cell Immunotherapy in Cancer

et al. 2018

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Increasing immunological knowledge and advances in techniques lay the ground for more efficient and broader application of immunotherapies. gamma delta (γδ) T-cells possess multiple favorable anti-tumor characteristics, making them promising candidates to be used in cellular and combination therapies of cancer. They recognize malignant cells, infiltrate tumors, and depict strong cytotoxic and pro-inflammatory activity. Here, we focus on human Vγ9Vδ2 T-cells, the most abundant γδ T-cell subpopulation in the blood, which are able to inhibit cancer progression in various models in vitro and in vivo. For therapeutic use they can be cultured and manipulated ex vivo and in the following adoptively transferred to patients, as well as directly stimulated to propagate in vivo. In clinical studies, Vγ9Vδ2 T-cells repeatedly demonstrated a low toxicity profile but hitherto only the modest therapeutic efficacy. This review provides a comprehensive summary of established and newer strategies for the enhancement of Vγ9Vδ2 T-cell anti-tumor functions. We discuss data of studies exploring methods for the sensitization of malignant cells, the improvement of recognition mechanisms and cytotoxic activity of Vγ9Vδ2 T-cells. Main aspects are the tumor cell metabolism, antibody-dependent cell-mediated cytotoxicity, antibody constructs, as well as activating and inhibitory receptors like NKG2D and immune checkpoint molecules. Several concepts show promising results in vitro, now awaiting translation to in vivo models and clinical studies. Given the array of research and encouraging findings in this area, this review aims at optimizing future investigations, specifically targeting the unanswered questions.

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Inversion of the Vδ1 to Vδ2 γδ T cell ratio in CVID is not restored by IVIg and is associated with immune activation and exhaustion

Abstract: Supplemental Digital Content is available in the text

Cited by 14 publications

References 36 publications

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

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

Common Variable Immunodeficiency: Epidemiology, Pathogenesis, Clinical Manifestations, Diagnosis, Classification, and Management

Improving the Efficiency of Vγ9Vδ2 T-Cell Immunotherapy in Cancer

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