Aberrant Regulation of Synovial T Cell Activation by Soluble Costimulatory Molecules in Rheumatoid Arthritis

Abstract

T cell activation and function are critically regulated by positive and negative costimulatory molecules. Aberrant expression and function of costimulatory molecules have been associated with persistent activation of self-reactive T cells in autoimmune diseases such as rheumatoid arthritis (RA). In this study, initial analysis of costimulatory molecules led to the unexpected observation that, in addition to CD80, several negative regulators (e.g., CTLA-4, programmed death-1 (PD-1), and PD ligand-1) were overexpressed in synovial T cells and macrophages derived from RA patients as opposed to controls. The expression of CD80 and PD ligand-1 on monocytes could be induced in vitro by IFN-γ and TNF-α that were produced abundantly in RA-derived synovial fluid (SF). Furthermore, the soluble form of negative costimulatory molecules occurred at high concentrations in sera and SF of RA patients and correlated with titers of rheumatoid factor in RA patients. In particular, the levels of soluble PD-1 were found to correlate significantly with those of TNF-α in SF derived from RA patients. Detailed characterization of soluble PD-1 revealed that it corresponded to an alternative splice variant (PD-1Δex3) and could functionally block the regulatory effect of membrane-bound PD-1 on T cell activation. Our data indicate a novel pathogenic pathway in which overexpression of negative costimulatory molecules to restrict synovial inflammation in RA is overruled by the excessive production of soluble costimulatory molecules.

Serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death ligand 1 (sPD-L1) in advanced pancreatic cancer

“…As seen in autoimmune disorders, we observed a close positive correlation of sPD-1 and sPD-L1 levels in patients with advanced PC, suggesting a common provenience and regulation of sPD-1 and sPD-L1 in cancer patients. 25 While sPD-L1 has not been determined in PC before, conflicting findings on the prognostic relevance of membrane bound PD-L1 on PC tumor cells exist. 7,35 Using a cox regression model including established prognostic factors for patients with advanced PC, we did not find an adverse influence of sPD-1 or sPD-L1 on OS.…”

“…The soluble forms of PD-1 and PD-L1 were initially described in autoimmune disorders where both sPD-1 and sPD-L1 are thought to be produced by immune cells upon stimulation with proinflammatory cytokines. 25,26 To the best of our knowledge, sPD-1 and sPD- L1 have not yet been measured conjointly in any cancer type. As seen in autoimmune disorders, we observed a close positive correlation of sPD-1 and sPD-L1 levels in patients with advanced PC, suggesting a common provenience and regulation of sPD-1 and sPD-L1 in cancer patients.…”

Comparison of biomarkers for systemic juvenile idiopathic arthritis

“…PD-L1, an immunoregulatory protein, is upregulated in rheumatoid arthritis (23), inflammatory bowel disease (24), and infection (16,17). Gene expression profiles may be affected by differing leukocyte composition in individual patients.…”

Regulation of Th1 and Th17 Cell Differentiation and Amelioration of Experimental Autoimmune Encephalomyelitis by Natural Product Compound Berberine

“…It is well established that APCs are critical for the full activation of T cells by Ag presentation through the tricomplex of MHC, Ag, and TCR and the expression and function of costimulatory molecules, such as CD80, CD86, and programmed death-ligand 1 (PD-L1) (27). These costimulatory molecules interact with corresponding ligands on Th1 and Th17 cells to provide a complete signal that is required for full action of T cells (9,28).…”