Chemokine Signaling Defects in Human Immunodeficiency

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WHIM syndrome is an autosomal dominant disease causing hypogammaglobulinernia, congenital neutropenia, variable T cell deficiency, and an unusual predisposition to human papillomavirus infection. Molecular genetic studies in patients with the disease have localized the trait locus to chromosome 2q21 and revealed truncating mutations in the gene encoding the chemokine receptor CXCR4. Signaling through the mutant receptors was enhanced in patient-derived lymphoblastoid cells, consistent with an activating mechanism. The receptor and its ligand are well studied because of their roles in HIV cell entry during infection and in B cell development and lymphoid tissue organization. Absence of the receptor compromises early B cell survival, but lymphocyte defects in patients carrying truncated CXCR4 receptors are not simply quantitative, raising the possibility of failure to migrate to the appropriate developmental compartment and/or maturation defects. This proposal will focus on establishing the effect of truncation mutations at the level of chemotaxis, signal transduction, and beta-arrestin-mediated receptor internalization in human and genetically modified murine cells expressing mutant CXCR4 receptors. Intracellular signaling following CXCR4 activation by CXCL12 is complex, involving multiple effectors. Preliminary evidence suggests that regulation of G-protein-coupled and ERK1/2 signaling is impaired in WHIM syndrome disease cells. Biochemical analysis of signaling pathways implicated in CXCR4 signaling and chemotaxis will be performed in B cells at distinct stages of maturation. In vitro studies will be coupled to determination of the in vivo effect of CXCR4 mutations on lymphoid organ development. In addition to providing insight into the disease pathophysiology, the resulting data will provide additional information on the role of the receptor tail domain in the developmental regulation of receptor responsiveness. The proposed studies share with Project 2 of the Program Project application a focus on mechanisms of hypogammaglobulinemia in immunodeficiency diseases and the possible role of migration defects in disease pathophysiology.