CD58 (LFA-3) stimulation provides a signal for human isotype switching and IgE production distinct from CD40.
Induction of an IgE response involves several discrete steps: 1) induction of epsilon germ line transcription, 2) DNA recombination, and 3) mature RNA transcription/translation. Here we show that ligation of B cell CD58 by CD2, its natural ligand on T cells, or by mAb, provides a novel IL-4-dependent signal for the latter two steps. Highly purified human B cells were induced to produce IgE by costimulation with IL-4 and CD58 mAb. Although CD58 ligation alone was unable to induce epsilon germ-line transcription, in concert with IL-4-stimulated epsilon germ-line transcription it induced the appearance of productive epsilon transcripts and IgE production. The direct involvement of CD2 was demonstrated: B cells cultured with IL-4 plus murine T hybridoma cells transfected with human CD2 produced IgE. A CD40 Fc fusion protein had no effect on CD58-driven IgE production while inhibiting CD40-dependent responses. Furthermore, cells from patients with common variable immunodeficiency produced IgE in response to IL-4 plus CD40 mAb but not to IL-4 plus CD58 mAb. CD58-driven IgE synthesis was IFN-gamma independent and was not enhanced by exogenous IL-6. Functional differences between CD40 and CD58 IgE stimulation were demonstrated. Thus, the CD2:CD58 ligand/counterligand system provides an alternative pathway by which cell contact signaling may regulate IgE. Given the relative importance of CD2 triggering on mucosal T cells and the mucosal location of IgE production, this may be especially true on mucosal surfaces.
Diaz-Sanchez
D
D
Hart and Louise Lyon Laboratory, Department of Medicine, UCLA School of Medicine 90024-1680.
Chegini
S
S
Zhang
K
K
Saxon
A
A
D000328:Adult; D015703:Antigens, CD / Q000502:physiology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000502:physiology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D018801:CD2 Antigens; D019013:CD40 Antigens; D018968:CD58 Antigens; D017074:Common Variable Immunodeficiency / Q000276:immunology; D017931:DNA Primers / Q000737:chemistry; D006801:Humans; D017578:Immunoglobulin Class Switching; D007073:Immunoglobulin E / Q000096:biosynthesis*; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis; D007371:Interferon-gamma / Q000502:physiology; D015847:Interleukin-4 / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000502:physiology*; D008875:Middle Aged; D008969:Molecular Sequence Data; D011940:Receptor Aggregation; D011971:Receptors, Immunologic / Q000502:physiology; D015398:Signal Transduction
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D000945:Antigens, Differentiation, T-Lymphocyte; D018801:CD2 Antigens; D019013:CD40 Antigens; D018968:CD58 Antigens; D017931:DNA Primers; D007132:Immunoglobulin Isotypes; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma