Exhaustion of bacteria-specific CD4 T cells and microbial translocation in common variable immunodeficiency disorders

Perreau, Matthieu; Viganó, Selena; Bellanger, Florence; Pellaton, Céline; Buss, Guillaume; Comte, Denis; Roger, Thierry; Lacabaratz, Christine; Bart, Pierre‐Alexandre; Lévy, Yves; Pantaleo, Giuseppe

doi:10.1084/jem.20140039

Cited by 104 publications

(106 citation statements)

References 54 publications

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“…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. This suggests that microbial translocation may underlie several perturbations in CVID and possibly explain some of the similarities in T cell anomalies between CVID and HIV infection (11).…”

Section: Discussionmentioning

confidence: 99%

“…In HIV type 1 and human T cell leukemia virus type 1 infections, MAIT cells are reduced in number and display impaired functionality in response to bacterial stimulation (27)(28)(29). Microbial translocation is now recognized to have a major role in HIV immuno-pathogenesis, and recent evidence suggests that microbial translocation could be responsible for CD4 + T cell exhaustion in CVID patients (30). Elevated levels of LPS in CVID are also associated with dysbiosis of the gut microbiota (31).…”

Section: Introductionmentioning

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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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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“…Phenotypic and functional defects of CD4 + T cells in CVID patients have been reported during the last decade [35][36][37]. These abnormalities include increased activated CD4 + T-cell counts and decreased total, naive, and memory CD4 + T-cell counts (Table 2), along with functional impairment, such as reduced proliferative capacity and failure in cytokine production [37,38].…”

Section: Cd4 + T-cell Defects In Cvidmentioning

confidence: 99%

“…These abnormalities include increased activated CD4 + T-cell counts and decreased total, naive, and memory CD4 + T-cell counts (Table 2), along with functional impairment, such as reduced proliferative capacity and failure in cytokine production [37,38]. This reduction in CD4 + T-cell counts is associated with a decrease in thymic output, increase in T-cell turnover, and spontaneous apoptosis [12].…”

Section: Cd4 + T-cell Defects In Cvidmentioning

confidence: 99%

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T-Cell Abnormalities in Common Variable Immunodeficiency

Azizi

Rezaei

Kiaee

et al. 2016

J Investig Allergol Clin Immunol

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Common variable immunodeficiency (CVID) is the most common clinical primary immunodeficiency. It is characterized by a defect in B-cell differentiation to plasma and memory B cells. Moreover, numerous T-cell abnormalities have been reported and include decreased T-cell count and proliferative response, increased T-cell activation and apoptosis, and abnormalities in cytokine production. The aims of this review are to describe phenotypic and functional defects in T cells in CVID patients and to review the literature with respect to the effects of immunoglobulin replacement on the T-cell component in CVID patients. Key words: Common variable immunodeficiency. T cell. Helper T cells. Regulatory T cells. ResumenLa inmunodeficiencia común variable (CVID) es la inmunodeficiencia primaria más frecuente. Se caracteriza por un defecto en la diferenciación de linfocitos B hacia células plasmáticas y linfocitos B memoria. Se han descrito numerosas alteraciones en los linfocitos T de estos pacientes, tales como disminución en el número de linfocitos T y en sus respuestas proliferativas, aumento en la activación de células T y en la apoptosis, así como alteraciones en la producción de citokinas. El objetivo de esta revisión es describir las alteraciones funcionales y fenotípicas de los linfocitos T en los pacientes con CVID y revisar la bibliografía en relación a los efectos que la administración de inmunoglobulinas produce en los linfocitos T de los pacientes con CVID. Palabras clave: Inmunodeficiencia común variable. Células T. Células T helper. Células T reguladoras.

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Gut commensal microbes do not represent a dominant antigenic source for continuous CD4⁺ T‐cell activation during HIV‐1 infection

et al. 2015

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Chronic immune activation is a hallmark of HIV-1 infection; specifically, the activation of T cells has predictive value for progression to AIDS. The majority of hyperactivated T cells are not HIV-specific and their antigenic specificities remain poorly understood.Translocation of gut luminal microbial products to systemic sites contributes to chronic immune activation during HIV-1 infection, but how it affects (TCR-dependent) immune activation remains elusive. We hypothesized that gut luminal antigens foster activation of CD4 + T cells with specificities for commensal bacterial antigens, thereby contributing to the pool of activated CD4 + T cells in the circulation of HIV-1 infected individuals. To test this hypothesis, we quantified the frequencies of gut microbe-specific CD4 + T cells by cytokine production upon restimulation with selected gut commensal microbial antigens. Contrary to our hypothesis, we did not observe increased but rather decreased frequencies of gut microbe-specific CD4 + T cells in HIV-1 infected individuals compared to healthy controls. We conclude that the increased activation status of circulating CD4 + T cells in HIV-1 infected individuals is not driven by CD4 + T cells with specificities for commensal bacterial antigens.Keywords: Gut microbe-specific CD4 + T-cell responses · IBD and HIV-1 associated enteropathy · Microbial translocation · Systemic immune activation Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionChronic activation of the immune system is a major determinant of progression to AIDS [1] and particularly the level of hyperactivated T cells is considered as best prognostic marker for disease Correspondence: Dr. Annette Oxenius e-mail: aoxenius@micro.biol.ethz.ch progression [2]. HIV-1 infection and replication is the main driving force of persistent, pathological level of T-cell activation [1,3] but HIV-1 specific T cells account for only a small fraction of activated T cells [4][5][6], implicating substantial "bystander" activation. Multiple mechanisms are considered to contribute to the genesis of such extensive immune activation, many of them are related to HIV-1 associated immunodeficiency [7,8] Immunol. 2015. 45: 3107-3113 HIV-1-related immunodeficiency leads to the reactivation of ubiquitous symbiotic viruses (e.g. herpes viruses), generating HIVunrelated antigens [7,8]. Furthermore, the rapid and irreversible depletion of intestinal CD4 + T cells, in particular Th17 cells that are essential for maintaining barrier function [10,11] during HIV-1 infection impair the integrity of the intestinal barrier and enable the translocation of commensal microbes (or their products) from the gut lumen to systemic sites [9]. Thus, HIV-1 replication, HIV-1-associated immunodeficiency [7,8], and microbial translocation [9] fuel a milieu rich of viral and bacterial pathogenassociated molecular patterns and proteins that have the capacity to activate innate and adaptive immune cells by engaging pattern re...

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Exhaustion of bacteria-specific CD4 T cells and microbial translocation in common variable immunodeficiency disorders

Cited by 104 publications

References 54 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

T-Cell Abnormalities in Common Variable Immunodeficiency

Gut commensal microbes do not represent a dominant antigenic source for continuous CD4⁺ T‐cell activation during HIV‐1 infection

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Exhaustion of bacteria-specific CD4 T cells and microbial translocation in common variable immunodeficiency disorders

Cited by 104 publications

References 54 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

T-Cell Abnormalities in Common Variable Immunodeficiency

Gut commensal microbes do not represent a dominant antigenic source for continuous CD4+ T‐cell activation during HIV‐1 infection

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Gut commensal microbes do not represent a dominant antigenic source for continuous CD4⁺ T‐cell activation during HIV‐1 infection