Defective T-cell activation caused by impairment of the TNF receptor 2 costimulatory pathway in common variable immunodeficiency

Aspalter, Rosa; Eibl, Martha M.; Wolf, Hermann M.

doi:10.1016/j.jaci.2007.07.004

Cited by 22 publications

(19 citation statements)

References 42 publications

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“…For example, it has been reported that TNFR2 promotes the activation and proliferation of mouse and human CD4 T cells upon TCR stimulation181937. In human common variable immunodeficiency patients, defective T cell activation is attributable to the impairment of the TNFR2 costimulatory pathway38. Furthermore, our results are most compatible with the report that transfer of TNFR2-over expressing naive CD4 cells into lymphopenic mice led to an earlier wasting syndrome, a more severe colitis and augmented Th1 cytokine production34.…”

Section: Discussionsupporting

confidence: 91%

TNFR2 expression by CD4 effector T cells is required to induce full-fledged experimental colitis

Chen

Nie

Xiao

et al. 2016

Sci Rep

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There is now compelling evidence that TNFR2 is constitutively expressed on CD4+ Foxp3+ regulatory T cells (Tregs) and TNF-TNFR2 interaction is critical for the activation, expansion and functional stability of Tregs. However, we showed that the expression of TNFR2 was also up-regulated on CD4+ Foxp3− effector T cells (Teffs) upon TCR stimulation. In order to define the role of TNFR2 in the pathogenic CD4 T cells, we compared the effect of transferred naïve CD4 cells from WT mice and TNFR2−/− mice into Rag 1−/− recipients. Transfer of TNFR2-deficient Teff cells failed to induce full-fledged colitis, unlike WT Teffs. This was due to defective proliferative expansion of TNFR2-deficient Teff cells in the lymphopenic mice, as well as their reduced capacity to express proinflammatory Th1 cytokine on a per cell basis. In vitro, the proliferative response of TNFR2 deficient naïve CD4 cells to anti-CD3 stimulation was markedly decreased as compared with that of WT naïve CD4 cells. The hypoproliferative response of TNFR2-deficient Teff cells to TCR stimulation was associated with an increased ratio of p100/p52, providing a mechanistic basis for our findings. Therefore, this study clearly indicates that TNFR2 is important for the proliferative expansion of pathogenic Teff cells.

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Section: Discussionsupporting

confidence: 91%

TNFR2 expression by CD4 effector T cells is required to induce full-fledged experimental colitis

Chen

Nie

Xiao

et al. 2016

Sci Rep

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“…CD40L have an important role in delivering functional signals in both CD4 + and CD8 + T cells [78], since a defect in the amplification of TCRderived activation by costimulatory signals could be responsible for impaired T-cell activation and defective amplification of TCR-dependent signal transduction in CVID patients [79,80]. Aspalter et al [81] also found significant selective impairment in costimulatory TNF-receptor II (TNF-R II) signaling events that resulted in reduced TRAF1 expression and TCR/TNF-RII-driven T-cell proliferation [81]. The above-mentioned studies proposed defects of TCR signaling and costimulation, thereby elucidating the molecular basis of T-cell defects in CVID patients [82].…”

Section: T-cell Signaling-associated Surface Molecules and The Resultmentioning

confidence: 99%

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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“…18 These newer therapeutic targets have complex and variable effects on T-cell activation, and current therapeutics aimed at any one of these targets have varying interactions with the inflammatory environment, highlighting the urgency to develop tools to both investigate relationships of immune-modulating networks in vivo and monitor the immune-based effects of therapy in patients. 19-26 …”

Section: Introductionmentioning

confidence: 99%

In Vivo PET Imaging of the Activated Immune Environment in a Small Animal Model of Inflammatory Arthritis

et al. 2017

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Background:Evolving immune-mediated therapeutic strategies for rheumatoid arthritis (RA) may benefit from an improved understanding of the complex role that T-cell activation plays in RA. This study assessed the potential of fluorine-18-labeled 9-β-d-arabinofuranosylguanine ([18F]F-AraG) positron emission tomography (PET) imaging to report immune activation in vivo in an adjuvant-induced arthritis (AIA) small animal model.Methods:Using positron emission tomography–computed tomography imaging, uptake of [18F]F-AraG in the paws of mice affected by arthritis at 6 (acute) and 20 (chronic) days following AIA induction in a single paw was assessed and compared to uptake in contralateral control paws. Fractions of T cells and B cells demonstrating markers of activation at the 2 time points were determined by flow cytometry.Results:Differential uptake of [18F]F-AraG was demonstrated on imaging of the affected joint when compared to control at both acute and chronic time points with corresponding changes in markers of T-cell activation observed on flow cytometry.Conclusion:[18F]F-AraG may serve as an imaging biomarker of T-cell activation in inflammatory arthritis. Further development of this technique is warranted and could offer a tool to explore the temporal link between activated T cells and RA as well as to monitor immune-mediated therapies for RA in clinical trials.

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Defective T-cell activation caused by impairment of the TNF receptor 2 costimulatory pathway in common variable immunodeficiency

Cited by 22 publications

References 42 publications

TNFR2 expression by CD4 effector T cells is required to induce full-fledged experimental colitis

TNFR2 expression by CD4 effector T cells is required to induce full-fledged experimental colitis

T-Cell Abnormalities in Common Variable Immunodeficiency

In Vivo PET Imaging of the Activated Immune Environment in a Small Animal Model of Inflammatory Arthritis

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