The immunoglobulin (Ig)alpha and Igbeta cytoplasmic domains are independently sufficient to signal B cell maturation and activation in transgenic mice.
The B cell antigen receptor, composed of membrane immunoglobulin (Ig) sheathed by the Igalpha/Igbeta heterodimer plays a critical role in mediating B cell development and responses to antigen. The cytoplasmic tails of Igalpha and Igbeta differ substantially but have been well conserved in evolution. Transfection experiments have revealed that, while these tails share an esssential tyrosine-based activation motif (ITAM), they perform differently in some but not all assays and have been proposed to recruit distinct downstream effectors. We have created transgenic mouse lines expressing chimeric receptors comprising an IgM fused to the cytoplasmic domain of each of the sheath polypeptides. IgM/alpha and IgM/beta chimeras (but not an IgM/beta with mutant ITAM) are each independently sufficient to mediate allelic exclusion, rescue B cell development in gene-targeted Igmu- mice that lack endogenous antigen receptors, as well as signal for B7 upregulation. While the (IgM/alpha) x (IgM/beta) double-transgenic mouse revealed somewhat more efficient allelic exclusion, our data indicate that each of the sheath polypeptides is sufficient to mediate many of the essential functions of the B cell antigen receptor, even if the combination gives optimal activity.
Teh
Y M
YM
Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 2QH, United Kingdom.
Neuberger
M S
MS
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen; D019281:Dimerization; D005434:Flow Cytometry; D018796:Immunoconjugates; D007075:Immunoglobulin M / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D016393:Lymphoma, B-Cell; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D011947:Receptors, Antigen, B-Cell / Q000096:biosynthesis* / Q000737:chemistry / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D014443:Tyrosine
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007075:Immunoglobulin M; D007376:Interleukin-2; D011947:Receptors, Antigen, B-Cell; D011993:Recombinant Fusion Proteins; D014443:Tyrosine; D000069594:Abatacept