Variations in Gnai2 and Rgs1 expression affect chemokine receptor signaling and the organization of secondary lymphoid organs

Abstract

Ligand bound chemoattractant receptors activate the heterotrimeric G protein Gi to stimulate downstream signaling pathways to properly position lymphocytes in lymphoid organs. Here we show how variations the expression of a chemokine receptor and in two components in the signaling pathway, Gαi2 and RGS1, affects the output fidelity of the signaling pathway. Examination of B cells from mice with varying numbers of intact alleles of Ccr7, Rgs1, Gnai2, and Gnai3 provided the basis for these results. Loss of a single allele of either Gnai2 or Rgs1 affected CCL19 triggered chemotaxis, while loss of a single allele of Ccr7, which encodes the cognate CCL19 receptor, had little effect. Emphasizing the importance of Gnai2, B cells lacking Gnai3 expression responded to chemokines better than did wild type B cells. At an organismal level, variations in Rgs1 and Gnai2 expression affected marginal zone B cell development, splenic architecture, lymphoid follicle size, and germinal center morphology. Gnai2 expression was also needed for the proper alignment of MOMA-1+ macrophages and MAdCAM-1+ endothelial cells along marginal zone sinuses in the spleen. These data indicate that chemoattractant receptors, heterotrimeric G-proteins, and RGS protein expression levels have a complex inter-relationship that affects the responses to chemoattractant exposure.