Genetic background influences Th cell differentiation by controlling the capacity for IL-2-induced IL-4 production by naive CD4+ T cells.
Comparative studies using T(h)2-prone BALB/c and T(h)1-prone C57BL/6 mice were performed to clarify the influence of genetic background on T(h) cell differentiation. The results showed IL-4, the production of which is induced by IL-2, to be much more abundantly produced by BALB/c naive CD4(+) T cells than by C57BL/6 naive CD4(+) T cells, thereby leading to a tendency for differentiation toward T(h)2 in BALB/c naive CD4(+) T cells. This difference in IL-4 production between the two naive CD4(+) T cells appeared to be attributable to specific intracellular signaling events. Signal transducer and activator of transcription 5 (STAT5) was preferentially activated by IL-2 in CD4(+) T cells developing in BALB/c in contrast to the corresponding cells in C57BL/6. In addition, IL-4 also induced stronger STAT5 activation in CD4(+) T cells developing in BALB/c than in those developing in C57BL/6, whereas STAT6 was equally activated in these two cells. Further results supported the involvement of STAT5 in the difference in T(h) cell differentiation between BALB/c and C57BL/6 naive CD4(+) T cells. STAT5A(-)(/)(-) naive CD4(+) T cells with the BALB/c genetic background showed markedly less IL-2-induced IL-4 production than BALB/c naive CD4(+) T cells. Conversely, forced expression of the constitutively active forms of STAT5A and STAT5B in C57BL/6 naive CD4(+) T cells promoted the differentiation of T(h)2 cells. Thus, our results indicate IL-2-induced IL-4 production by naive CD4(+) T cells, in which STAT5 activation is involved and directly controlled by the genetic background, to influence T(h) cell differentiation in murine strains.
Yagi
Junji
J
Department of Microbiology and Immunology, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. jyagi1@research.twmu.ac.jp
Arimura
Yutaka
Y
Takatori
Hiroaki
H
Nakajima
Hiroshi
H
Iwamoto
Itsuo
I
Uchiyama
Takehiko
T
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D005786:Gene Expression Regulation; D007376:Interleukin-2 / Q000378:metabolism / Q000502:physiology*; D015847:Interleukin-4 / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D013045:Species Specificity; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology*
D007376:Interleukin-2; D050799:STAT5 Transcription Factor; D015847:Interleukin-4