Rapid induction of a novel costimulatory activity on B cells by CD40 ligand.
BACKGROUND
T cells and B cells communicate by direct cell--cell interaction that is crucial to the functioning of the immune system. It is well established that the interaction between B-cell-expressed CD40 and T-cell-expressed CD40 ligand (CD40L) is critical for T-cell-dependent antibody responses, but the role of this interaction in T-cell responses is less clear. In this study, we have used mice with targeted mutations in the genes encoding CD40L or CD28 to investigate how the CD40-CD40L interaction induces on B cells a costimulatory activity that acts in addition to antigen to trigger T-cell growth.


RESULTS
We show that T cells from Cd40L-deficient mice induce a substantially reduced costimulatory activity on B cells compared to wild-type T cells, particularly at early time points. Surprisingly, T cells, from CD40L-deficient mice induce similar levels of B7-1 and B7-2 as do wild-type T cells. We further show that the CD40L-mediated induction of costimulatory activity precedes the induction of B7-1, B7-2 and the heat-stable antigen (HSA). CD4 T cells isolated from the CD28-deficient mice can receive costimulatory activity from CD40L-induced B cells, demonstrating that the induced molecules can costimulate T cells by a CD28-independent mechanism. We have generated a novel monoclonal antibody that inhibits the CD40L-induced costimulatory activity. Expression of the epitope detected by this monoclonal antibody correlates with the induction of the costimulatory activity, and the molecule recognized by the monoclonal antibody is a single chain of around 85 kDa, distinct from B7-1, B7-2, ICAM-1, ICAM-2, ICAM-3, HSA CD5, integrin and 4-1BB ligand.


CONCLUSIONS
Our results demonstrate that CD40L is both necessary and sufficient for rapid, T-cell-mediated induction of costimulatory activity on B cells. This costimulatory activity is distinct from B7-1 and B7-2, and is independent of CD28.
Wu
Y
Y
Michael Heidelberger Division of Immunology, Department of Pathology, New York University Medical Center, New York 10016, USA.
Xu
J
J
Shinde
S
S
Grewal
I
I
Henderson
T
T
Flavell
R A
RA
Liu
Y
Y
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D023201:CD40 Ligand; D002455:Cell Division; D002460:Cell Line; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D016296:Mutagenesis
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; D008562:Membrane Glycoproteins; D023201:CD40 Ligand