Methotrexate Restores CD73 Expression on Th1.17 in Rheumatoid Arthritis and Psoriatic Arthritis Patients and May Contribute to Its Anti-Inflammatory Effect through Ado Production

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.

Surface AMP deaminase 2 as a novel regulator modifying extracellular adenine nucleotide metabolism

“…Correspondingly, polymorphisms causing reduced AMPD activity were associated with enhanced responsiveness to MTX, while low CD39 expression in Tregs caused the opposite 131,132 . Bossennec et al found that MTX treatment was indeed associated with increased ADO production by T H cells from RA patients 96 . Nevertheless, we did not observe changes in eAMPD2 expression after incubation with MTX.…”

“…131,132 Bossennec et al found that MTX treatment was indeed associated with increased ADO production by T H cells from RA patients. 96 Nevertheless, we did not observe changes in eAMPD2 expression after incubation with MTX. Importantly, it has to be considered that-in vivo-several immunomodulatory effects only manifest after up to three months of MTX therapy.…”

“…We thus concluded that this upregulation might indeed represent an anti-inflammatory mechanism supported by GC treatment. As the immunomodulatory effects of MTX have been described to be partly modulated by changes in ectonucleotidase function, [95][96][97] we exploratorily examined PBMCs after incubation with 0.8 µM MTX (corresponding to plasma levels achieved by weekly application of 15 mg MTX) 98 for 24 hours in comparison with untreated control samples or in the presence of LPS. We found that ectoenzyme expression remained unaffected by MTX treatment (Figure 5C+D).…”

Clinical efficacy and safety of methotrexate compared with leflunomide in the treatment of rheumatoid arthritis

“…[10] (2) Regulating the balance of Th1/Th2 and Th17/Treg, thus to inhibit chronic synovitis. [11,12] (3) Regulating adenosine-related pathways and inhibiting synovitis of RA. [13] (4) Inhibiting the expression of MMP-1, MMP-2, and other MMPs, so as to inhibit the destruction of joint bone.…”

The Biomarkers of Cd4+ T Regulatory Cells Associated with Tumour Immune Escape

“…CD39+CD73+ cancer cells inhibited the proliferation of CD4 and CD8 T cells and the generation of cytotoxic effector CD8 T cells in a CD39-and adenosine-dependent manner [69]. Through cooperation between CD39+ Treg and CD73+ expressing Th1/Th17 subset in breast cancer [70] Adenosine derived from the degradation of ATP via ectonucleotidases CD39 and CD73 is a critical immunosuppressive metabolite in the hypoxic microenvironment of tumor tissue and Adenosine signaling via A2aR can inhibit the antitumor immune response of CD8+ T cells [70][71][72][73]. The generation of adenosine by CD73 also suppresses antitumor immune responses through the activation of A2A receptors on T cells and natural killer cells [74][75][76] [10] Colorectal [17][18][19][20] Gastric [9,18] Head and neck squamous cell carcinoma [26] Lung [8] Non-small lung cancer [12][13][14][15][16] Oral squamous cells carcinoma [22,23] Pediatric B-cell acute lymphocytic leukemia [24] Prostate [25] Urinary bladder [5] IL-2, IL-10, IL-12, IL-35 [10,28] IFN-γ [10,21] TGF-β [24,27,28] tumour necrosis factor receptor type-11 [19] CCR5,CCR7 and their ligands CCL5, CCL19 and CCL21 [32] PD-L1 [13,23] PD-L1/CTLA-4 [18] PD-1/CD39 [18] CTLA-4 [13] LAG...…”