Stat5a regulates T helper cell differentiation by several distinct mechanisms.
We have previously shown that CD4(+) T cell-mediated allergic inflammation is diminished in signal transducer and activator of transcription (Stat)5a-deficient (Stat5a(-/-)) mice. To determine whether Stat5a regulates T helper cell differentiation, we studied T helper (Th)1 and Th2 cell differentiation of Stat5a(-/-)CD4(+) T cells at single-cell levels. First, Th2 cell differentiation from antigen-stimulated splenocytes was significantly decreased in Stat5a(-/-) mice as compared with that in wild-type mice. Further, Th2 cell differentiation was also impaired in Stat5a(-/-) mice even when purified CD4(+) T cells were stimulated with anti-CD3 plus anti-CD28 antibodies in the presence of interleukin-4. Moreover, the retrovirus-mediated gene expression of Stat5a in Stat5a(-/-)CD4(+) T cells restored the Th2 cell differentiation at the similar levels to that in wild-type CD4(+) T cells. In addition, interleukin-4 normally phosphorylated Stat6 in CD4(+) T cells from Stat5a(-/-) mice. Second, the development of CD4(+)CD25(+) immunoregulatory T cells was impaired in Stat5a(-/-) mice, as indicated by a significant decrease in the number of CD4(+)CD25(+) T cells in Stat5a(-/-) mice. Furthermore, the depletion of CD4(+)CD25(+) T cells from wild-type splenocytes significantly decreased Th2 cell differentiation but increased Th1 cell differentiation, whereas the depletion of CD4(+)CD25(+) T cells from Stat5a(-/-) splenocytes had no significant effect on the Th1 and Th2 cell differentiation. Together, these results indicate that the intrinsic expression of Stat5a in CD4(+) T cells is required for Th2 cell differentiation and that Stat5a is involved in the development of CD4(+)CD25(+) immunoregulatory T cells that modulate T helper cell differentiation toward Th2 cells.
Kagami
S
S
Department of Internal Medicine II, Chiba University School of Medicine, Japan.
Nakajima
H
H
Suto
A
A
Hirose
K
K
Suzuki
K
K
Morita
S
S
Kato
I
I
Saito
Y
Y
Kitamura
T
T
Iwamoto
I
I
D000818:Animals; D015704:CD4 Antigens / Q000032:analysis; D002453:Cell Cycle; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000502:physiology*; D015870:Gene Expression; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008894:Milk Proteins; D015375:Receptors, Interleukin-2 / Q000032:analysis; D011993:Recombinant Fusion Proteins / Q000502:physiology; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000166:cytology; D018417:Th1 Cells / Q000166:cytology* / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology* / Q000378:metabolism; D015534:Trans-Activators / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*
D015704:CD4 Antigens; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; C494093:Stat5a protein, mouse; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4