Rap1b regulates B cell development, homing, and T cell-dependent humoral immunity.
Rap1 is a small GTPase that belongs to Ras superfamily. This ubiquitously expressed GTPase is a key regulator of integrin functions. Rap1 exists in two isoforms: Rap1a and Rap1b. Although Rap1 has been extensively studied, its isoform-specific functions in B cells have not been elucidated. In this study, using gene knockout mice, we show that Rap1b is the dominant isoform in B cells. Lack of Rap1b significantly reduced the absolute number of B220(+)IgM(-) pro/pre-B cells and B220(+)IgM(+) immature B cells in bone marrow. In vitro culture of bone marrow-derived Rap1b(-/-) pro/pre-B cells with IL-7 showed similar proliferation levels but reduced adhesion to stromal cell line compared with wild type. Rap1b(-/-) mice displayed reduced splenic marginal zone (MZ) B cells, and increased newly forming B cells, whereas the number of follicular B cells was normal. Functionally, Rap1b(-/-) mice showed reduced T-dependent but normal T-independent humoral responses. B cells from Rap1b(-/-) mice showed reduced migration to SDF-1, CXCL13 and in vivo homing to lymph nodes. MZ B cells showed reduced sphingosine-1-phosphate-induced migration and adhesion to ICAM-1. However, absence of Rap1b did not affect splenic B cell proliferation, BCR-mediated activation of Erk1/2, p38 MAPKs, and AKT. Thus, Rap1b is crucial for early B cell development, MZ B cell homeostasis and T-dependent humoral immunity.
Chu
Haiyan
H
Laboratory of Molecular Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Awasthi
Aradhana
A
White
Gilbert C
GC
Chrzanowska-Wodnicka
Magdalena
M
Malarkannan
Subramaniam
S
D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D001853:Bone Marrow; D002448:Cell Adhesion; D049109:Cell Proliferation; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D008198:Lymph Nodes; D051379:Mice; D018345:Mice, Knockout; D013154:Spleen; D013601:T-Lymphocytes / Q000276:immunology; D020668:rap GTP-Binding Proteins / Q000502:physiology*
C492136:Rap1b protein, mouse; D020668:rap GTP-Binding Proteins