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

Background

Patients with common variable immunodeficiency have defective T-cell activation after stimulation via T-cell receptor (TCR)/CD28 or by recall antigens.

Objective

In the current study, we investigated whether TNF–receptor 2 (RII) costimulation, which is important for sufficient TCR/CD28 stimulation, was significantly impaired in common variable immunodeficiency (CVID).

Methods

We studied T-cell activation events such as CD69 induction, calcium flux through store operated calcium channels, protein kinase C-θ translocation, and costimulation via TNF-RII compared with costimulation via CD28.

Results

By measuring TNF receptor–associated factor 1 expression, which is induced by TCR alone and can be upregulated by either CD28 or TNF-RII costimulation, we show that costimulation via CD28 is intact, whereas costimulation via TNF-RII in these patients is impaired. The ras-activation pathway as tested by CD69 induction, calcium flux through store operated calcium channels, and protein kinase C-θ translocation were comparable in CVID and control T cells.

Conclusion

Taken together, these data indicate that the primary TCR signal as well as the signal derived from CD28 are normal but that TNF-RII–supported TCR costimulation is defective, most likely leading to impairment of an important amplification loop, such as TNF-RII augmented nuclear factor-κB activation.

Clinical implications

The finding of defective TNF-RII cosignaling in patients with CVID may help to define the activation pathway affected, thus potentially leading to a characterization of the molecular defect and molecular diagnosis in at least some of these patients.

Key words: CVID, primary immunodeficiency, T-cell receptor, TNF-α, TNF-RII, TRAF1, calcium flux, store operated calcium channels, PKC-θ

Abbreviations used: CVID, Common variable immunodeficiency, PKC, Protein kinase C, PMA, Phorbol 12-myristate 13-acetate, SOC, Store-operated calcium, TCR, T-cell receptor, TNF-RII, TNF–receptor 2 (p75, CD120b), TRAF, TNF receptor–associated factor