Abstract:
:The class IA subgroup of phosphoinositide 3-kinase (PI3K) is activated downstream of antigen receptors, costimulatory molecules, and cytokine receptors on lymphocytes. Targeted deletion of individual genes for class IA regulatory subunits severely impairs the development and function of B cells but not T cells. Here we analyze conditional mutant mice in which thymocytes and T cells lack the major class IA regulatory subunits p85alpha, p55alpha, p50alpha, and p85beta. These cells exhibit nearly complete loss of PI3K signaling downstream of the T-cell receptor (TCR) and CD28. Nevertheless, T-cell development is largely unperturbed, and peripheral T cells show only partial impairments in proliferation and cytokine production in vitro. Both genetic and pharmacologic experiments suggest that class IA PI3K signaling plays a limited role in T-cell proliferation driven by TCR/CD28 clustering. In vivo, class IA-deficient T cells provide reduced help to B cells but show normal ability to mediate antiviral immunity. Together these findings provide definitive evidence that class IA PI3K regulatory subunits are essential for a subset of T-cell functions while challenging the notion that this signaling mechanism is a critical mediator of costimulatory signals downstream of CD28.
journal_name
Bloodjournal_title
Bloodauthors
Deane JA,Kharas MG,Oak JS,Stiles LN,Luo J,Moore TI,Ji H,Rommel C,Cantley LC,Lane TE,Fruman DAdoi
10.1182/blood-2006-07-038620subject
Has Abstractpub_date
2007-04-01 00:00:00pages
2894-902issue
7eissn
0006-4971issn
1528-0020pii
blood-2006-07-038620journal_volume
109pub_type
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