title: Cd1d regulates B cell development but not B cell accumulation and IL10 production in mice with pathologic CD5(+) B cell expansion.
abstract: BACKGROUND
  CD1d is a widely expressed lipid antigen presenting molecule required for CD1d-restricted invariant natural killer T (iNKT) cell development. Elevated CD1d expression is detected in CD5(+) IL10-producing B cells, called B10 B cells, and is correlated with poorer prognosis in chronic lymphocytic leukemia (CLL), a CD5(+) B cell malignancy with B10-like functional properties. Whether CD1d expression regulates CD5(+) B cell accumulation, IL10 competence, and antibody production in naïve mice with pathologic CD5(+) B cell expansion remains untested.
  
  
  RESULTS
  Using three different transgenic mouse models of benign or leukemic CD5(+) B cell expansion, we found that CD1d was differentially expressed on CD5(+) B cells between the three models, but loss of CD1d expression had no effect on CD5(+) B cell abundance or inducible IL10 expression in any of the models. Interestingly, in the CLL-prone Eμ-TCL1 model, loss of CD1d expression suppressed spontaneous IgG (but not IgM) production, whereas in the dnRAG1xEμ-TCL1 (DTG) model of accelerated CLL, loss of CD1d expression was associated with elevated numbers of splenic CD4(+) and CD8(+) T cells and an inverted CD4(+):CD8(+) T cell ratio. Unexpectedly, before leukemia onset, all three transgenic CD1d-deficient mouse strains had fewer splenic transitional B cells than their CD1d-proficient counterparts.
  
  
  CONCLUSIONS
  The results show that CD1d expression and iNKT cells are dispensable for the development, accumulation, or IL10 competence of CD5(+) B cells in mice prone to benign or leukemic CLL-like B cell expansion, but reveal a novel role for iNKT cells in supporting B cell progression through the transitional stage of development in these animals. These results suggest CD1d-directed therapies to target CLL could be evaded by downregulating CD1d expression with little effect on continued leukemic CD5(+) B cell survival. The data also imply that iNKT cells help restrain pro-leukemic CD8(+) T cell expansion in CLL, potentially explaining a reported correlation in human CLL between disease progression, the loss of NKT cells, and a paradoxical increase in CD8(+) T cells.
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University, 2500 California Plaza, Omaha, NE, 68178, USA. VictoriaFaust@creighton.edu.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Palmer
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University, 2500 California Plaza, Omaha, NE, 68178, USA. VincentNganga@creighton.edu.
authors.forename: Vincent K
authors.initials: VK
authors.lastname: Nganga
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University, 2500 California Plaza, Omaha, NE, 68178, USA. MaryRothermund@creighton.edu.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Rothermund
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University, 2500 California Plaza, Omaha, NE, 68178, USA. gap00438@creighton.edu.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Perry
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University, 2500 California Plaza, Omaha, NE, 68178, USA. pswanson@creighton.edu.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Swanson
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D055610:Antigens, CD1d / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D018956:CD5 Antigens / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D055610:Antigens, CD1d; D018956:CD5 Antigens; D018398:Homeodomain Proteins; D007074:Immunoglobulin G; D007075:Immunoglobulin M; C064658:RAG-1 protein; D016753:Interleukin-10