CD19 cytoplasmic tyrosines 482 and 513 mediating binding to PI3K are sufficient to reconstitute the T-dependent humoral immune response (IRM8P.713)

Abstract

Abstract CD19 is a co-stimulatory receptor on B cells that has been shown to play a critical role in regulating B cell differentiation and the humoral immune response. In mice lacking CD19 expression, B1 and marginal zone (MZ) B cell subpopulations are absent and the T-dependent humoral response is severely impaired in association with defective GC B cell generation and GC responses resulting in loss of class switching, affinity maturation and ultimately the failure to generate Ag-specific memory B cells and Ab secreting cells (ASC) that produce class switched, high affinity Abs. Previous studies have demonstrated the selective mutation of tyrosines 482 and 513 (4/5F mice) in the cytoplasmic domain of CD19 is sufficient to recapitulate the phenotype associated with complete loss of CD19 expression. In the present study, mice were generated in which CD19 is expressed containing only Y482 and Y513 in the absence of the other seven cytoplasmic tyrosine residues (4/5Y mice). Analysis of 4/5Y mice revealed that these residues alone are sufficient to restore B1 and MZ B cell development as well as the T-dependent humoral immune response. Studies to examine mice expressing CD19 with a selective mutation to either tyrosine 482 or 513 revealed a preferential requirement for tyrosine 482 to promote a normal humoral response. These data support the conclusion that CD19 predominantly contributes to normal B cell development and the T-dependent humoral response through its recruitment of PI3K.