Abstract
Objectives: Th1.17 are highly polyfunctional, potentially harmful CD4+ effector T cells (Teff) through IFN-γ and IL-17A coproduction. Th1.17 take part in the pathophysiology of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), in which their hyper activation results in part from defects in negative regulation mechanisms. We recently demonstrated that the ecto-nucleotidase CD73 delineates a Th1.17-enriched Teff population and acts as an endogenous regulatory mechanism. Because Methotrexate (MTX), used as first line treatment of RA and PsA, increases extracellular concentrations of AMP and immunosuppressive adenosine, we investigated the modulation of CD73 by MTX treatment on Teff in RA/PsA patients. Methods: In a prospective cohort of 26 RA and 15 PsA patients before or under MTX treatment, we evaluated CD73 expression on blood Teff subsets, their cytokine production and AMPase functions. Results: We showed a decreased CD73 expression on Th1.17 and Th1 in untreated patients compared to healthy donors that was partly restored under MTX. This decrease in untreated patients leads to a halved Ado production by Th1.17 cells. CD73+ Teff remained functional under MTX treatment, but their CD73 re-expression may contribute to control their activation. Conclusion: Our study unveils uncovered mode of action of MTX on Teff subsets modulation and in the adenosine-dependent termination of inflammation in RA and PsA.
Highlights
Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA) are chronic inflammatory disorders characterized by tenderness and swelling of the joints
Peripheral Blood Mononuclear Cells (PBMC) were activated with PMA and Ionomycin (Sigma-Aldrich) as previously described [12] and intracellular cytokines (IL-17A, TNF-α, IFN-γ, IL-22) produced by CD73+ and CD73neg Teff were analyzed using the specific panel described in Table S1 (Panel C)
Total memory CD4+ and CD8+ T cells frequencies were not modified in peripheral blood of untreated RA and PsA patients compared to healthy donors (HD) (Figure S2A), neither were frequencies of T helper lymphocytes (Th) subpopulations based on their CCR6 and CXCR3 expression [23] (Figure 1A)
Summary
Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA) are chronic inflammatory disorders characterized by tenderness and swelling of the joints. PsA is usually associated with the skin condition psoriasis (Pso) [2] In both cases, study of the immune infiltrate of inflamed joints has shed light on deleterious memory CD4+ T helper lymphocytes (Th): Th17 and Th1.17 [3,4,5]. Study of the immune infiltrate of inflamed joints has shed light on deleterious memory CD4+ T helper lymphocytes (Th): Th17 and Th1.17 [3,4,5] These cells, found enriched at the inflamed site, secrete high amounts of the pro-inflammatory cytokine IL-17A, responsible for many features of both RA and PsA. In the context of chronic inflammation, modulation of expression of these ecto-enzymes on Teff, and of Ado production, may regulate T cell activation. CD73 expression level on Teff may represent a therapeutic target worth considering in the treatment of RA by restoring and stabilizing it through an immunosuppressive feedback loop enabling Ado production
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