CD28 co-stimulation is intact and contributes to prolonged ex vivo survival of hyporesponsive synovial fluid T cells in rheumatoid arthritis.

Abstract:

:In rheumatoid arthritis (RA), T cells in the inflamed joint are considered to play a crucial role in the pathogenesis. However, despite the fact that synovial T cells have an activated memory phenotype, they are functionally suppressed upon combined CD3 and CD28 stimulation. Here, we analyzed the contribution of both CD3 and CD28 to the hyporesponsiveness of synovial T cells in RA. In contrast to the low CD3 responsiveness of synovial fluid (SF) T cells compared to peripheral blood (PB) T cells, the CD28 co-stimulatory response was observed to be unaffected. Hyporesponsiveness of SF T cells has previously been associated with decreased levels of intracellular glutathione (GSH), an antioxidant and regulator of the intracellular redox state. Treatment of SF T cells with N-acetylcysteine, an antioxidant and replenisher of GSH, selectively improved CD3-induced responses, while leaving CD28 responsiveness unaffected. These data show that the CD3 pathway is highly sensitive to intracellular GSH alterations, whereas CD28 responsiveness is relatively refractory. Furthermore, in support for a functional role of CD28 co-stimulation, it was demonstrated that CD28 ligation acted in synergy with the IL-2 receptor gamma chain signaling cytokine IL-15 in the enhancement of the ex vivo survival of SF T cells. These data indicate that CD28 co-stimulatory capacity of SF T cells, in contrast to CD3 stimulation, remains intact despite an altered intracellular redox state. Thereby, CD28 stimulation may contribute to the persistence of T cells at the site of inflammation, which might be of relevance in the pathogenesis of RA.

journal_name

Eur J Immunol

authors

Maurice MM,van der Voort EA,Leow A,Levarht N,Breedveld FC,Verweij CL

doi

10.1002/(SICI)1521-4141(199805)28:05<1554::AID-IMM

subject

Has Abstract

pub_date

1998-05-01 00:00:00

pages

1554-62

issue

5

eissn

0014-2980

issn

1521-4141

pii

10.1002/(SICI)1521-4141(199805)28:05<1554::AID-IMM

journal_volume

28

pub_type

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