期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 106, 期 48, 页码 20371-20376出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0911573106
关键词
CD28; follicular B helper T-cell; germinal center; ICOS; PI3K
资金
- Canadian Institutes for Health Research
- Vascular System Research Center
- Korea Science and Engineering Foundation
- Canadian Institutes of Health Research
- National Research Foundation of Korea [2001-0036405] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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