Effects of conventional immunosuppressive treatment on CD244+ (CD28null) and FOXP3+ T cells in the inflamed muscle of patients with polymyositis and dermatomyositis

Abstract

BackgroundT-cell infiltrates may persist in muscle tissue of polymyositis (PM) and dermatomyositis (DM) patients despite aggressive immunosuppressive treatment. Here, we investigated to what extent persistent T cells in affected muscle were FOXP3+, a marker for regulatory T cells (Tregs), or CD244+, a marker for CD28null T cells, and whether their presence correlated to clinical outcome. The sensitivity of CD28null T cells towards glucocorticoid and Treg-mediated immunosuppression was also investigated.MethodsMuscle biopsies from 16 newly diagnosed or untreated patients with PM/DM were investigated by immunohistochemistry for expression of CD3, FOXP3 and CD244 before and after treatment with glucocorticoids and immunosuppressive agents. For clinical evaluation, serum levels of creatine kinase, muscle performance (FI and MMT8), disease activity (MITAX) and disability (HAQ) were measured. In vitro suppressive effects of glucocorticoids and Tregs on T-cell activation were measured by CD69 upregulation.ResultsBefore treatment, CD244+ cells were present at higher proportions compared to FOXP3+ cells in the inflamed muscle. Following treatment, FOXP3+ cell numbers decreased while CD244+ cells persisted. Patients with impaired muscle function (<75 % FI) post-treatment had higher levels of CD244+ cells in the follow-up biopsy compared to those with FI >75 %. MITAX and HAQ correlated with the number of CD244+ cells post-treatment. CD4+CD28null T cells displayed lower sensitivity towards both glucocorticoid and Treg-mediated immunosuppression in vitro compared to their CD28+ counterparts.ConclusionsPoor outcome in patients with myositis following immunosuppressive therapy was linked to persistence of CD244+ (CD28null) T cells in muscle tissue, suggesting their resistance against immunosuppression. A relative loss of regulatory T cells could also contribute to poor clinical outcome given their recently ascribed role in muscle tissue regeneration.

Abatacept in the treatment of adult dermatomyositis and polymyositis: a randomised, phase IIb treatment delayed-start trial

“…We have previously shown a decrease in number of Foxp3 + cells in the muscle tissue of patients with myositis  on treatment with glucocorticoids 19. This difference could be related to the different treatment targets since tissue-resident Foxp3 + Tregs have been implicated in muscle repair and regeneration 20 21.…”

The host defense peptide LL-37 a possible inducer of the type I interferon system in patients with polymyositis and dermatomyositis

“…CD58/CD2 was reported as a primarily replaced costimulatory pathway in human CD8 + CD28 null T cells in vitro [135]. After treatment with glucocorticoids a higher frequency of CD28 null T cells was found in muscle tissue of patients with myositis, compared to the reduced frequency of Tregs [136].…”

CD4+ and CD8+ CD28null T Cells Are Cytotoxic to Autologous Muscle Cells in Patients With Polymyositis

“…It has also been demonstrated that CD28 null T cell proliferation and function was only partly suppressed by regulatory T cells (18). In addition, CD41CD28 null T cells are less sensitive to glucocorticoid-mediated suppression (19). Such reduced sensitivity to glucocorticoids could be due to expression of antiapoptotic molecules (20,21), alternative signaling pathways and costimulatory receptors (22,23), and/or lower expression of glucocorticoid receptors (24).…”