OR3: an anti-TCR autoantibody and immunomodulation (96.7)

Abstract

Abstract The presence of low levels of circulating self-reactive autoantibodies (AAbs) is a normal feature of a healthy immune system. One suggested function for autoantibodies is the control of autoreactivity and immune homeostasis. Healthy humans spontaneously express low levels of serum AAbs directed against defined epitopes of the T Cell Receptor (TCR) Vβ chains that can be markedly elevated in individuals with autoimmune diseases such as Rheumatoid Arthritis (RA). Here, we describe a monoclonal IgM AAb, OR3, derived from peripheral blood B cells of a patient with RA. OR3 was selected for its ability to bind to residues 23-38 of the complementarity determining region 1 (CDR1) segment of human Vβ8.1. It binds to Jurkat T cells expressing human Vβ8.1 and to ovalbumin-specific transgenic murine DO11.10 T cells. OR3 significantly reduces ova peptide stimulated activation of DO11.10 CD4+ T cells and inhibits IFN-γ, IL-2 and IL-10 cytokine secretion by antigen specific DO11.10 T cells. OR3 also blocks antigen induced proliferation of DO11.10 T cells, but does not initiate apoptosis. The interaction between the TCR and MHC:peptide is a critical point in the activation of the adaptive immune response, disruption of which, can lead to a global dampening of the immune response. We show evidence for the development of a unique anti-TCR autoantibody that binds to only a subset of T cells and possesses potent blocking and anti-inflammatory properties that can be harnessed for therapeutic use.