Improvement of T-cell function in rheumatoid arthritis (RA) patients in clinical remission is associated with the recovery of IL-7 expression and depends on a familial history of RA

Background

Rheumatoid arthritis (RA) is a chronic, inflammatory disease with a number of phenotypic and functional T-cell defects. We previously demonstrated abnormal differentiation and hyperproliferation of RA patient T cells [1], in relation with inflammation and associated with reduced thymic activity as measured by T-cell recepter excision circle (TREC) content. However, it is still not clear whether these dysfunctions are a primary feature of RA or only secondary to inflammation. Therefore we analysed RA patients in clinical remission in whom systemic inflammation was controlled.

Methods

Patients were defined as 'in remission' when they had controlled disease, with no change of activity for at least 6 months, C-reactive protein below 15, no swollen or tender joints and on stable treatment (with or without therapy). Measurements of TREC content in CD4⁺ T cells was by real-time PCR. IL-7 quantification was by ELISA. Proliferation assay in response to mitogen, IL-2, TCR stimulation or recall antigen.

Results

The TREC content of CD4⁺ T cells in these patients was heterogeneous (n = 35). However, two groups of patients could be defined: group 1 (TREC rich), similar to healthy controls (n = 17); group 2 (TREC poor), close to active disease (n = 19). No conventional clinical parameter such as age, sex, disease duration, remission duration, treatment, clinical scores or rheumatoid factor could explain this difference. However, age at disease onset was significantly distributed between these two groups (P = 0.021) and correlated with a familial maternal history of RA. IL-7 is essential to thymic T-cell development and to T-cell activation in the periphery. We found large variations in IL-7 circulating levels between RA patients in remission (n = 57). There was a positive correlation between the circulating levels of IL-7 and the TREC content (r = 0.701, P < 0.0001), suggesting that recovery of thymic activity was limited by the availability of IL-7. We investigated T-cell responses to mitogen, antigen, recall antigen and IL-2 in patients with high and low levels of circulating IL-7 (n = 5 for each group). Low levels of IL-7 were associated with hyporesponsiveness to all stimuli, which could be overcome by adding IL-7 to the cultures. In contrast, high levels of IL-7 were associated with optimal responses to all stimuli including recall antigen and were not greatly ameliorated by supplementing IL-7.

Conclusion

RA patients in clinical remission are clearly separated in two groups, according to their ability to express IL-7 and the associated consequences on thymic activity and T-cell responses. This ability was dependent on the age of the patients at disease onset. This was only associated with a maternal family history of RA and suggests that genetic anticipation may be involved.