All ETDs from UAB

Advisory Committee Chair

Randall S Davis

Advisory Committee Members

Peter D Burrows

Louis B Justement

Robinna G Lorenz

Allan J Zajac

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Members of the Fc receptor-like (FCRL) family are cell-surface proteins with ancient conservation, distinct lymphocyte expression patterns, and tyrosine-based signaling capa-bilities that imply a fundamental role for them in modulating immune responses. Though they share many features with the Fc receptors (FCR) for IgG and IgE, FCRLs have not been found to bind immunoglobulin. In these studies, we sought to characterize the cellu-lar expression pattern, binding partner, and function of a recently identified FCRL family member, human FCRL6. By developing specific monoclonal antibodies (mAbs) we determined that FCRL6 is dis-tinctly expressed by cytotoxic lymphocytes, namely NK cells, CD8+ T cells, γδ T cells, and rare cytotoxic CD4+ T cells. To elucidate its extracellular ligand(s), a cell-based GFP reporter system was developed to assay FCRL6 surface receptor engagement. These stud-ies revealed that FCRL6 binds to HLA-DR, an MHC class II molecule. This interaction was confirmed by generating a panel of HLA-DR-reactive mAbs that blocked the FCRL6/HLA-DR association and by demonstrating that soluble recombinant FCRL6-Fc molecules specifically bind to HLA-DR transductants. The functional relevance of this discovery was also examined. First, by blocking the FCRL6/HLA-DR interaction, CD8+ T cell functions could be enhanced in response to antigenic peptide stimulation. Second, forced expression of FCRL6 in a human NK cell line inhibited its killing of HLA-DR-expressing cells. Collectively, these studies demonstrate that FCRL6, a molecule dis-tinctly expressed by cytotoxic lymphocytes, inhibits their effector function upon engage-ment of its ligand, MHC class II. These findings reveal an intriguing evolutionary rela-tionship between receptors for immunoglobulin and MHC and demonstrate that NK cells and CD8+ T cells, whose activities are traditionally considered to be governed by MHC class I interactions, are also functionally regulated by MHC class II. This newfound inter-face may have important implications for better understanding HLA class II disease asso-ciation and its manipulation could be of therapeutic benefit to patients with disorders of cell-mediated immunity.

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