Dysregulation of CD30+ T cells by leukemia impairs isotype switching in normal B cells.
Chronic lymphocytic leukemia (CLL) is associated with impaired immunoglobulin (Ig) class-switching from IgM to IgG and IgA, a defect that leads to recurrent infections. When activated in the presence of leukemic CLL B cells, T cells rapidly up-regulate CD30 through an OX40 ligand and interleukin 4 (IL-4)-dependent mechanism. These leukemia-induced CD30+ T cells inhibit CD40 ligand (CD40L)-mediated S mu-->S gamma and S mu-->S alpha class-switch DNA recombination (CSR) by engaging CD30 ligand (CD30L), a molecule that interferes with the assembly of the CD40-tumor necrosis factor receptor-associated factor (TRAF) complex in nonmalignant IgD+ B cells. In addition, engagement of T cell CD30 by CD30L on neoplastic CLL B cells down-regulates the CD3-induced expression of CD40L. These findings indicate that, in CLL, abnormal CD30-CD30L interaction impairs IgG and IgA production by interfering with the CD40-mediated differentiation of nonmalignant B cells.
Cerutti
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A
Division of Molecular Immunology, Department of Pathology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA. acerutti@med.cornell.edu
Kim
E C
EC
Shah
S
S
Schattner
E J
EJ
Zan
H
H
Schaffer
A
A
Casali
P
P
D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D018106:CD28 Antigens / Q000378:metabolism; D053285:CD30 Ligand; D019013:CD40 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D002454:Cell Differentiation; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D006801:Humans; D007070:Immunoglobulin A / Q000096:biosynthesis; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007074:Immunoglobulin G / Q000096:biosynthesis; D066298:In Vitro Techniques; D015847:Interleukin-4 / Q000378:metabolism; D017730:Ki-1 Antigen / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D053278:OX40 Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D015854:Up-Regulation
D018106:CD28 Antigens; D053285:CD30 Ligand; D019013:CD40 Antigens; D016827:CD8 Antigens; D017931:DNA Primers; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D017730:Ki-1 Antigen; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D018124:Receptors, Tumor Necrosis Factor; C089251:TNFSF4 protein, human; C505774:TNFSF8 protein, human; D015847:Interleukin-4