Characterization of the Syk-Dependent T Cell Signaling Response to an Altered Peptide

Abstract

Rheumatoid Arthritis (RA) is an autoimmune disorder characterized by T cell dysregulation. We have shown that an altered peptide ligand (A9) activates T cells to utilize an alternate signaling pathway which is dependent upon FcRγ and Syk, resulting in downregulation of inflammation. In the experiments described herein we have attempted to determine the molecular basis of this paradox. Three major SFKs found in T cells (Lck, Fyn, and Lyn) were tested for activation following stimulation by A9/I-Aq. Unexpectedly we found they are not required for T cell functions induced by A9/I-Aq, nor are they required for APL stimulation of cytokines. On the other hand, the induction of the second messenger inositol trisphosphate (IP3) and the mobilization of calcium are clearly triggered by the APL A9/I-Aq stimulation and are required for cytokine production albeit the cytokines induced are different from those produced after activation of the canonical pathway. DBA/1 mice doubly deficient in both IL-4 and IL-10 were used to confirm that these two cytokines are important for the APL-induced attenuation of arthritis. These studies provide a basis for exploring the effectiveness of analog peptides and the inhibitory T cells they induce as therapeutic tools for autoimmune arthritis.

The role of Syk in peripheral T cells

“…The exact mechanism for A12 immunosuppression has not been definitively established but there is substantial circumstantial evidence that it exerts its effects through activation of an alternative signaling pathway. We have previously shown that an altered peptide ligand (A9) which is restricted by the murine I-A q -can activate T cells to utilize an FCRγ-dependent alternative signaling pathway (8–10). In the present experiments we address two important questions.…”