T-cell function is partially maintained in the absence of class IA phosphoinositide 3-kinase signaling

Author:

Deane Jonathan A.1,Kharas Michael G.1,Oak Jean S.1,Stiles Linda N.1,Luo Ji23,Moore Travis I.1,Ji Hong4,Rommel Christian4,Cantley Lewis C.23,Lane Thomas E.15,Fruman David A.15

Affiliation:

1. Department of Molecular Biology and Biochemistry, University of California, Irvine;

2. Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA;

3. Department of Systems Biology, Harvard Medical School, Boston, MA;

4. Serono Pharmaceutical Research Institute, Geneva, Switzerland;

5. Center for Immunology, University of California, Irvine

Abstract

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 p85α, p55α, p50α, and p85β. 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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