Diversity of T Lymphocytes in Rheumatoid Arthritis

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a disease of an aberrant immune response in a genetically predisposed host that leads to chronic progressive synovial inflammation, destruction of the joint architecture, and extraarticular manifestations. Of critical importance is the recognition of antigen by CD4 T cells in restriction to disease-associated MHC class II molecules. It is the central hypothesis of this application that these T-cell responses are regulated by stimulatory and inhibitory receptors that recognize self-MHC class I molecules. Previous studies have focused on the biological behavior of clonal populations of T cells in RA that likely reflect stimulation with persisting antigens or autoantigens. Unexpectedly, CD4 T-cell clones expanded in vivo lose the expression of the costimulatory molecules, CD28 and CD40 ligand, and acquire the expression of killer-cell immunoglobulin-like receptors (KIR). The clinical relevance of this differentiation step is suggested by the finding that the frequencies of CD4+CD28null t-cells correlate with extraarticular manifestations of RA and the rate of erosive progression. The fate of a T-cell stimulatory signal in these T-cell clones depends on: 1) the coordinate recognition of MHC class I by KIRs and MHC class II by T-cell receptors in supramolecular microdomains: and 2) the balance of inhibitory and stimulatory receptors expressed on individual T-cell clones. We propose that this balance is skewed towards the activity of stimulatory receptors in RA. In this proposal, experiments have been designed to test this hypothesis by investigating the function of KIRs in adoptive transfer studies in a human synovium-mouse chimera model (Specific Aim 1a). To assess the in vivo function of KIRs in patients with RA, KIR expression will be correlated with disease activity and severity and with T-cell turnover (Specific Aim 1b and c). Specific Aim 2 will focus on the transcriptional control of inhibitory and stimulatory KIRs to investigate observation that one stimulatory KIR, KIR2DS2, is preferentially expressed on CD4 T cells from patients with RA. KIR2DS2 triggering appears to induce a different signaling pathway in T cells than in NK cells. Specific Aim 3 will explore the hypothesis that KIR2DS2 activates the stress-related kinase system through an unknown adaptor molecular. Finally, Specific Aim 4 will explore the coordinate recognition of MHC class I and class II molecules by determining the involvement of stimulatory and inhibitory KIRs in the T-cell synapse. The long-term goal of this proposal is to determine whether this novel regulatory system of stimulatory and inhibitory receptors can be exploited for therapeutic interventions to control disease-relevant T-cell responses in RA.