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

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

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).

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

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-theta translocation were comparable in CVID and control T cells.

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-kappaB activation.

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.