Background/Purpose:

Polymyositis (PM) and dermatomyositis (DM) are characterized by infiltration of T cells and macrophages in skeletal muscle tissue. Conventional immunosuppressive treatment has limited effects on infiltrating cells. In this context, CD28null T cells are interesting, which display properties of proinflammatory killer cells and are suggested to be resistant to apoptosis in vivo. Recently, it was found in our lab that after conventional glucocorticoid treatment, the relative number of regulatory T cells (Treg) was unchanged or decreased, while the CD28null T cell proportion was mainly increased in muscle tissue of myositis patients. (Loell et al; ACR 2011, Arthritis Rheum 2011;63 Suppl 10 :233). This leads to our working hypothesis that CD28null T cells are resistant to immunosuppression mediated by glucocorticoids in the setting of myositis. An additional explanation could be a lack of sensitivity in the CD28null population towards Treg mediated suppression.

The aim of this study was to investigate the clinical relevance of persistent CD28null T cells in myositis patients treated with glucocorticoids and to further evaluate immunosuppressive effects of both glucocorticoids and Treg on CD28null T cells in vitro.

Methods:

Immunohistochemistry for CD3, FOXP3 and CD28null surrogate marker CD244 was performed on muscle tissue obtained from 14 patients with PM/DM, treated with glucocorticoids and additional immunosuppressive drugs for 8 (4-16) months. For clinical evaluation, muscle performance was measured by Functional Index at biopsy time points. Post treatment 5 years follow up for disease activity was done by Myositis Intention To Treat Activity Index (MITAX). In vitro immunosuppression assays were performed on anti-CD3 activated PBMCs from 6 myositis patients and 6 healthy donors. To quantify % suppression, reduction in CD69 (early T cell activation marker) on activated T cells upon glucocorticoid and Treg addition was measured by flow cytometry.

Results:

At group level, patients improved in Functional Index measurement. However, patients with Functional Index <75% post treatment were found to display higher level of CD244+(CD28null) T cells (median 14,cells/mm², p=0.01) in post treatment muscle biopsies compared to those with high Functional Index (>75%) (median 1 cell/mm²). Patient disease activity MITAX correlated with the number of CD244+ cells/mm² post treatment (Rho=0.74, p=0.04). In in vitro immunosuppression assays, CD4+CD28null T cells displayed lower sensitivity towards glucocorticoid-mediated suppression (median suppression: patients 46.8%, healthy 51.6%) compared to CD28+ counterparts (68.5%, 80.7%) in both myositis patients and healthy donors. CD4+CD28null T cells were also less sensitive than CD28+ counterparts towards Treg mediated suppression (median: 18% versus 57.2%). No clear trend could be observed in CD8+ compartment. 

Conclusion:

Above in vivo and in vitro findings suggest that poor outcome from the glucocorticoid therapy in myositis patients is linked to persistence of CD28null T cells in muscle tissue, which are relatively resistant to both glucocorticoid and Treg mediated immunosuppression.

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« Back to 2013 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/role-of-muscle-persistent-cd28null-t-cells-in-glucocorticoid-therapy-resistance-in-myositis-patients/