CD28 costimulation accelerates IL-4 receptor sensitivity and IL-4-mediated Th2 differentiation.
The development of Th1 and Th2 cells is determined by the type of antigenic stimulation involved in the initial cell activation step. Evidence indicates that costimulatory signals, such as those delivered by CD28, play an important role in Th2 development, but little is known about how CD28 costimulation contributes to Th2 development. In this study, TCR cross-linking was insufficient for Th2 development, while the addition of CD28 costimulation drastically increased Th2 generation through the IL-4-mediated pathway. Th2 generation following CD28 costimulation was not simply explained by the enhancement of IL-4 production in naive T cells. To generate Th2 cells after TCR cross-linking only, it was necessary to add a 20- to 200-fold excess of IL-4 generated after TCR and CD28 stimulation. TCR cross-linking increased the expression level and binding property of the IL-4R, but enhanced the sensitivity to IL-4 only slightly. In contrast, as evidenced by the enhanced phosphorylation of Jak3, the IL-4Ralpha-chain, and STAT6 following IL-4 stimulation, CD28 costimulation increased IL-4R sensitivity without affecting its expression and binding property. This evidence of the enhancement of IL-4R sensitivity increases our understanding of how CD28 costimulation accelerates Th2 development.
Kubo
M
M
Division of Immunobiology, Research Institute for Biological Sciences, Science University of Tokyo, Noda City, Chiba, Japan. raysolfc@rs.noda.sut.ac.jp
Yamashita
M
M
Abe
R
R
Tada
T
T
Okumura
K
K
Ransom
J T
JT
Nakayama
T
T
D000276:Adjuvants, Immunologic / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001665:Binding Sites / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D015847:Interleukin-4 / Q000502:physiology*; D053616:Janus Kinase 3; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000096:biosynthesis / Q000378:metabolism*; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3