title: Intrinsic unresponsiveness of Mertk-/- B cells to chronic graft-versus-host disease is associated with unmodulated CD1d expression.
abstract: Activation and migration of marginal zone B (MZB) cells into follicular (FO) regions of the spleen has been proposed as one of the mechanisms that regulate the development of autoreactive B cells. The mer receptor tyrosine kinase (Mertk) mediates apoptotic cell clearance and regulates activation and cytokine secretion. In the well-studied class II chronic GVH model of bm12 cells into B6 hosts, we observed that Mertk deficient B6 mice did not generate autoantibodies in response to this allogeneic stimulus. We posited that Mertk is important in MHC-II-mediated B cell signaling. In the present study, we show that B cells from Mertk(-/-) mice but not WT B6 mice exhibited decreased calcium mobilization and tyrosine phosphorylation when stimulated by MHC-II cross-linking. The finding that Mertk was important for class II signaling in B cells was further supported by the preponderance of a-allotype autoantibodies in cGVH in RAG-KO mice reconstituted with a mixture of bone marrow from Mertk(-/-) mice (b-allotype) and C20 mice (a-allotype). MZB cells from Mertk(-/-) mice were unable to down regulate surface CD1d expression and subsequent inclusion in the MZ, associated with significantly lower germinal center responses compared to MZB cells from WT. Moreover, Mertk(-/-) mice treated with an anti-CD1d down regulating antibody responded significantly to bm12 cells, while no response was observed in Mertk(-/-) mice treated with control antibodies. Taken together, these findings extend the role of Mertk to include CD1d down regulation on MZB cells, a potential mechanism limiting B cell activation in cGVH.
authors.affiliation: Section of Rheumatology, Department of Medicine, Temple University, Philadelphia PA 19140, USA.
authors.forename: Wen-Hai
authors.initials: WH
authors.lastname: Shao
authors.forename: Yuxuan
authors.initials: Y
authors.lastname: Zhen
authors.forename: Fred D
authors.initials: FD
authors.lastname: Finkelman
authors.forename: Robert A
authors.initials: RA
authors.lastname: Eisenberg
authors.forename: Philip L
authors.initials: PL
authors.lastname: Cohen
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000235:genetics / Q000276:immunology*; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D002908:Chronic Disease; D015870:Gene Expression / Q000276:immunology; D018858:Germinal Center / Q000276:immunology* / Q000473:pathology; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007126:Immunoglobulin Allotypes / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000473:pathology; D000076202:c-Mer Tyrosine Kinase
chemical_list: D055610:Antigens, CD1d; D001323:Autoantibodies; C526879:Cd1d1 protein, mouse; D007126:Immunoglobulin Allotypes; D011518:Proto-Oncogene Proteins; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D002118:Calcium