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 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.
Gigoux
Mathieu
M
Institut de recherches cliniques de Montréal, Montréal, Canada H2W 1R7.
Shang
Jijun
J
Pak
Youngshil
Y
Xu
Minghong
M
Choe
Jongseon
J
Mak
Tak W
TW
Suh
Woong-Kyung
WK
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism*; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D047468:Immunoprecipitation; D060889:Inducible T-Cell Co-Stimulator Protein; D015847:Interleukin-4 / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D000098546:Interleukin-21
D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D007378:Interleukins; D015847:Interleukin-4; D019869:Phosphatidylinositol 3-Kinases; D000098546:Interleukin-21