Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase

The T-cell costimulatory receptors, CD28 and the inducible costimulator (ICOS), are required for the generation of follicular B helper T cells (T(FH)) and germinal center (GC) reaction. A common signal transducer used by CD28 and ICOS is the phosphoinositide 3-kinase (PI3K). Although it is known tha...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 48; p. 20371
Main Authors: Gigoux, Mathieu, Shang, Jijun, Pak, Youngshil, Xu, Minghong, Choe, Jongseon, Mak, Tak W, Suh, Woong-Kyung
Format: Journal Article
Language:English
Published: United States 01.12.2009
Subjects:
Animals
Antigens, Differentiation, T-Lymphocyte - immunology
Antigens, Differentiation, T-Lymphocyte - metabolism
CD28 Antigens - immunology
CD28 Antigens - metabolism
CD4-Positive T-Lymphocytes - metabolism
Cell Differentiation - immunology
Enzyme-Linked Immunosorbent Assay
Immunoprecipitation
Inducible T-Cell Co-Stimulator Protein
Interleukin-4 - immunology
Interleukins - immunology
Mice
Mice, Transgenic
Phosphatidylinositol 3-Kinases - immunology
Phosphatidylinositol 3-Kinases - metabolism
Signal Transduction - immunology
T-Lymphocytes, Helper-Inducer - immunology
ISSN:1091-6490, 1091-6490
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Summary:The T-cell costimulatory receptors, CD28 and the inducible costimulator (ICOS), are required for the generation of follicular B helper T cells (T(FH)) and germinal center (GC) reaction. A common signal transducer used by CD28 and ICOS is the phosphoinositide 3-kinase (PI3K). Although it is known that CD28-mediated PI3K activation is dispensable for GC reaction, the role of ICOS-driven PI3K signaling has not been defined. We show here that knock-in mice that selectively lost the ability to activate PI3K through ICOS had severe defects in T(FH) generation, GC reaction, antibody class switch, and antibody affinity maturation. In preactivated CD4(+) T cells, ICOS delivered a potent PI3K signal that was critical for the induction of the key T(FH) cytokines, IL-21 and IL-4. Under the same settings, CD28 was unable to activate PI3K but supported a robust secondary expansion of T cells. Thus, our results demonstrate a nonredundant function of ICOS-PI3K pathway in the generation of T(FH) and suggest that CD28 and ICOS play differential roles during a multistep process of T(FH) differentiation.
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.0911573106