ICOS is critical for CD40-mediated antibody class switching.
The inducible co-stimulatory molecule (ICOS) is a CD28 homologue implicated in regulating T-cell differentiation. Because co-stimulatory signals are critical for regulating T-cell activation, an understanding of co-stimulatory signals may enable the design of rational therapies for immune-mediated diseases. According to the two-signal model for T-cell activation, T cells require an antigen-specific signal and a second, co-stimulatory, signal for optimal T-cell activation. The co-stimulatory signal promotes T-cell proliferation, lymphokine secretion and effector function. The B7-CD28 pathway provides essential signals for T-cell activation, but does not account for all co-stimulation. We have generated mice lacking ICOS (ICOS-/- ) to determine the essential functions of ICOS. Here we report that ICOS-/- mice exhibit profound deficits in immunoglobulin isotype class switching, accompanied by impaired germinal centre formation. Class switching was restored in ICOS-/- mice by CD40 stimulation, showing that ICOS promotes T-cell/B-cell collaboration through the CD40/CD40L pathway.
McAdam
A J
AJ
Departments of Pathology, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, Massachusetts 02115, USA.
Greenwald
R J
RJ
Levin
M A
MA
Chernova
T
T
Malenkovich
N
N
Ling
V
V
Freeman
G J
GJ
Sharpe
A H
AH
D000818:Animals; D000917:Antibody Formation; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000502:physiology*; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000502:physiology*; D023201:CD40 Ligand / Q000502:physiology; D018390:Gene Targeting; D018858:Germinal Center / Q000502:physiology; D006241:Haptens; D006433:Hemocyanins / Q000276:immunology; D017578:Immunoglobulin Class Switching; D007132:Immunoglobulin Isotypes; D060889:Inducible T-Cell Co-Stimulator Protein; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology
D000945:Antigens, Differentiation, T-Lymphocyte; D019013:CD40 Antigens; D006241:Haptens; C556694:Icos protein, mouse; D007132:Immunoglobulin Isotypes; D060889:Inducible T-Cell Co-Stimulator Protein; C054401:trinitrophenyl keyhole limpet hemocyanin; D023201:CD40 Ligand; D006433:Hemocyanins