Severely impaired B lymphocyte proliferation, survival, and induction of the c-Myc:Cullin 1 ubiquitin ligase pathway resulting from CD22 deficiency on the C57BL/6 genetic background.
Understanding the molecular mechanisms through which CD22 regulates B lymphocyte homeostasis, signal transduction, and tolerance is critical to defining normal B cell function and understanding the role of CD22 in autoimmunity. Therefore, CD22 function was examined in vivo and in vitro using B cells from CD22-deficient (CD22(-/-)) mice. Backcrossing of founder CD22(-/-) mice onto the C57BL/6 (B6) genetic background from a B6/129 mixed background resulted in a dramatically reduced B cell proliferative response following IgM ligation, characterized by a paucity of lymphoblasts and augmented apoptosis. Also, the phenotype of splenic B6 CD22(-/-) B cells was uniquely HSA(high) and IgD(low)/CD21(low) with intermediate levels of CD5 expression, although the percentages of mature and transitional B cells were normal. That B6 CD22(-/-) B cells predominantly underwent apoptosis following IgM ligation correlated with this unique tolerant phenotype, as well as defective induction of the c-Myc:Cullin 1 (CUL1) ubiquitin ligase pathway that is necessary for progression to the S phase of cell cycle. CD40 ligation compensated for CD22 deficiency by restoring lymphoblast development, proliferation, c-Myc and CUL1 expression, and protein ubiquitination/degradation in IgM-stimulated B6 CD22(-/-) B cell cultures. Thereby, this study expands our current understanding of the complex role of CD22 during B cell homeostasis and Ag responsiveness, and reveals that the impact of CD22 deficiency is dictated by the genetic background on which it is rendered. Moreover, this study defines CD22 and CD40 as the first examples of lymphocyte coreceptors that influence induction of the c-Myc:CUL1 ubiquitin ligase pathway.
Poe
Jonathan C
JC
Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
Haas
Karen M
KM
Uchida
Junji
J
Lee
Youngkyun
Y
Fujimoto
Manabu
M
Tedder
Thomas F
TF
D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000502:physiology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics* / Q000502:physiology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D044842:Cullin Proteins / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D004790:Enzyme Induction / Q000235:genetics / Q000276:immunology; D006131:Growth Inhibitors / Q000502:physiology; D007075:Immunoglobulin M / Q000502:physiology; D016130:Immunophenotyping; D037102:Lectins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000172:deficiency / Q000502:physiology; D051918:Sialic Acid Binding Ig-like Lectin 2; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis* / Q000172:deficiency / Q000502:physiology
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D044842:Cullin Proteins; D006131:Growth Inhibitors; D007075:Immunoglobulin M; D037102:Lectins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D051918:Sialic Acid Binding Ig-like Lectin 2; D044767:Ubiquitin-Protein Ligases; C497868:Cd22 protein, mouse; C100318:Cullin 1