Variations in Gnai2 and Rgs1 expression affect chemokine receptor signaling and the organization of secondary lymphoid organs.
Ligand bound chemoattractant receptors activate the heterotrimeric G-protein G(i) to stimulate downstream signaling pathways to properly position lymphocytes in lymphoid organs. Here, we show how variations in the expression of a chemokine receptor and in two components in the signaling pathway, Galpha(i2) and RGS1, affect 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, whereas the 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 interrelationship that affects the responses to chemoattractant exposure.
Hwang
I Y
IY
B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Park
C
C
Harrision
K A
KA
Huang
N N
NN
Kehrl
J H
JH
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D054415:Chemokine CCL19 / Q000276:immunology; D054377:Chemokine CXCL12 / Q000276:immunology; D054382:Chemokine CXCL13 / Q000276:immunology; D002633:Chemotaxis / Q000276:immunology; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D008221:Lymphoid Tissue / Q000033:anatomy & histology* / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D009088:Mucoproteins; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*
C515461:Ccl19 protein, mouse; C515371:Ccr7 protein, mouse; D015815:Cell Adhesion Molecules; D054415:Chemokine CCL19; D054377:Chemokine CXCL12; D054382:Chemokine CXCL13; C515256:Cxcl12 protein, mouse; C486386:Cxcl13 protein, mouse; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; D020710:RGS Proteins; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; C488188:Rgs1 protein, mouse; D051960:GTP-Binding Protein alpha Subunit, Gi2; C498016:Gnai2 protein, mouse