T-cell function is partially maintained in the absence of class IA phosphoinositide 3-kinase signaling.
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.
Deane
Jonathan A
JA
Department of Molecular Biology and Biochemistry, University of California, Irvine 92697-3900, USA.
Kharas
Michael G
MG
Oak
Jean S
JS
Stiles
Linda N
LN
Luo
Ji
J
Moore
Travis I
TI
Ji
Hong
H
Rommel
Christian
C
Cantley
Lewis C
LC
Lane
Thomas E
TE
Fruman
David A
DA
D000818:Animals; D049109:Cell Proliferation; D066298:In Vitro Techniques; D008211:Lymphocyte Cooperation; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000145:classification / Q000172:deficiency / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D021122:Protein Subunits; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D021122:Protein Subunits; D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse