The outcome of T-cell responses after T-cell encounter with specific antigens
is modulated by co-stimulatory signals, which are required for both lymphocyte
activation and development of adaptive ...immunity. ICOS, an inducible co-stimulator with homology to CD28, is expressed
on activated, but not resting T cells, and shows T-cell co-stimulatory
function in vitro. ICOS binds specifically to its counter-receptor
B7RP-1 (refs 5,6,7), but not to B7-1 or B7-2. Here we provide in vivo
genetic evidence that ICOS delivers a co-stimulatory signal that is essential
both for efficient interaction between T and B cells and for normal antibody
responses to T-cell-dependent antigens. To determine the physiological function
of ICOS, we generated and characterized gene-targeted ICOS-deficient mice.
In vivo, a lack of ICOS results in severely deficient T-cell-dependent
B-cell responses. Germinal centre formation is impaired and immunoglobulin
class switching, including production of allergy-mediating IgE, is defective.
ICOS-deficient T cells primed in in vivo and restimulated in vitro
with specific antigen produce only low levels of interleukin-4, but remain
fully competent to produce interferon-γ.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Costimulation through the inducible costimulator (ICOS) and its ligand (ICOSL) is essential for T cell-dependent B cell responses, but the cellular and temporal dynamics underlying its in vivo ...effects are poorly defined. Here we have shown that Icosl(-/-) and Icos(-/-) mice had similar phenotypes and that ICOS-ICOSL costimulation modulated the early but not late phases of IgG1 affinity maturation. Exploiting the adoptive transfer of T or B cells from primed Icosl(-/-) mice, we provided genetic evidence that costimulation through ICOSL was essential for primary but not secondary helper T cell responses and for the control of both T and B cell activities, resulting in T cell-dependent IgG1 production.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Previous work has shown ICOS can function independently of CD28, but whether either molecule can compensate for the other in vivo is not known. Since ICOS is a potent inducer of Th2 cytokines and ...linked to allergy and elevated serum IgE in humans, we hypothesized that augmenting ICOS costimulation in murine allergic airway disease may overcome CD28 deficiency. While ICOS was expressed on T cells from CD28
−/− mice, Th2-mediated airway inflammation was not induced in CD28
−/− mice by increased ICOS costimulation. Further, we determined if augmenting CD28 costimulation could compensate for ICOS deficiency. ICOS
−/− mice had a defect in airway eosinophilia that was not overcome by augmenting CD28 costimulation. CD28 costimulation also did not fully compensate for ICOS for antibody responses, germinal center formation or the development of follicular B helper T cells. CD28 and ICOS play complementary non-overlapping roles in the development of Th2 immunity in vivo.
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