Diversity of T Lymphocytes in Rheumatoid Arthritis

Project: Research project

Project Details


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.
StatusNot started


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