T cell receptor-induced calcineurin activation regulates T helper type 2 cell development by modifying the interleukin 4 receptor signaling complex.
The activation of downstream signaling pathways of both T cell receptor (TCR) and interleukin 4 receptor (IL-4R) is essential for T helper type 2 (Th2) cell development, which is central to understanding immune responses against helminthic parasites and in allergic and autoimmune diseases. However, little is known about how these two distinct signaling pathways cooperate with each other to induce Th2 cells. Here, we show that successful Th2 cell development depends on the effectiveness of TCR-induced activation of calcineurin. An inhibitor of calcineurin activation, FK506, inhibited the in vitro anti-TCR-induced Th2 cell generation in a dose-dependent manner. Furthermore, the development of Th2 cells was significantly impaired in naive T cells from dominant-negative calcineurin Aalpha transgenic mice, whereas that of Th1 cells was less affected. Efficient calcineurin activation in naive T cells upregulated Janus kinase (Jak)3 transcription and the amount of protein. The generation of Th2 cells induced in vitro by anti-TCR stimulation was inhibited significantly by the presence of Jak3 antisense oligonucleotides, suggesting that the Jak3 upregulation is an important event for the Th2 cell development. Interestingly, signal transducer and activator of transcription (STAT)5 became physically and functionally associated with the IL-4R in the anti-TCR-activated developing Th2 cells that received efficient calcineurin activation, and also in established cloned Th2 cells. In either cell population, the inhibition of STAT5 activation resulted in a diminished IL-4-induced proliferation. Moreover, our results suggest that IL-4-induced STAT5 activation is required for the expansion process of developing Th2 cells. Thus, Th2 cell development is controlled by TCR-mediated activation of the Ca(2+)/calcineurin pathway, at least in part, by modifying the functional structure of the IL-4R signaling complex.
Yamashita
M
M
Department of Developmental Immunology, Chiba University School of Medicine, Japan.
Katsumata
M
M
Iwashima
M
M
Kimura
M
M
Shimizu
C
C
Kamata
T
T
Shin
T
T
Seki
N
N
Suzuki
S
S
Taniguchi
M
M
Nakayama
T
T
D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression; D015847:Interleukin-4 / Q000378:metabolism; D053616:Janus Kinase 3; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008894:Milk Proteins; D008969:Molecular Sequence Data; D020319:Oligodeoxyribonucleotides, Antisense; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019948:Receptors, Interleukin-4 / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D018417:Th1 Cells / Q000166:cytology; D018418:Th2 Cells / Q000166:cytology / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D016693:Receptors, Antigen, T-Cell, alpha-beta; D019948:Receptors, Interleukin-4; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D015847:Interleukin-4; D011505:Protein-Tyrosine Kinases; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3; D019703:Calcineurin