B lymphocytes are the central mediators of humoral immunity. Aberrant B cell function contributes to many autoimmune diseases and age-related defects in humoral immunity, with malignant B lymphocytes representing the primary cell type in leukemia and lymphoma. B cell function is regulated through cell-surface molecules that generate transmembrane signals, regulate intercellular communication, and direct lymphocyte localization within tissues. Other than the B cell antigen receptor (BCR) complex, relatively very little is known about the function and signal transduction pathways of most B cell-surface proteins.
The aim of these studies is to examine the function of CD22, a B lymphocyte-specific cell-surface receptor. CD22 is a lectin-like member of the immunoglobulin superfamily that functions as an adhesion molecule for diverse sialylated cell-surface and soluble ligands. Ligand binding by CD22 may regulate both positive and negative effects of transmembrane signals generated through the BCR and CD19. Moreover, genetic alterations in CD22 ligand binding activity, structure, or expression may contribute to autoimmunity by altering its regulatory interactions with SHP 1 and SHIP, potent intracellular phosphatases. We propose that adhesion receptor function of CD22 regulates transmembrane signals and BCR-induced cell death in peripheral B cells. There are four specific aims designed to test this hypothesis and to further determine how CD22 regulates B cell function.
In specific aim 1, the functional significance and functional consequences of CD22 ligand binding will be assessed in vivo by analyzing new lines of mice, which express mutated cell-surface CD22 molecules that lack ligand-binding activity.
In specific aim 2, we will use B cells from CD22-deficient and -mutant mice to dissect how CD22 regulates B cell survival.
Specific Aim 3 will assess CD22 intracellular signal transduction pathways.
In specific aim 4, the role of CD22 in the development of an autoimmune repertoire will be assessed and we will determine whether CD22 engagement influences the age of onset or severity of autoantibody production. Since CD22 provides an important regulatory checkpoint for adjusting humoral immune responses, understanding CD22 function may provide mechanisms for modulating humoral immunity and the treatment of B cell abnormalities leading to immunodeficiency, autoimmunity or malignancy. ? ?
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