Polarized development of memory cell-like IFN-gamma-producing cells in the absence of TCR zeta-chain.
TCR/CD3 complex-mediated signals play critical roles in regulating CD4(+) Th cell differentiation. In this report, we have examined the in vivo role of a key TCR/CD3 complex molecule zeta-chain in regulating the differentiation of Th cells. We have studied T cells from zeta-chain-deficient mice (zetaKO mice), zeta-chain-bearing mice (zeta(+) mice), and from zetaKO mice expressing a FcRgamma chain transgene (FcRgammaTG, zetaKO mice). Our results demonstrated that, compared with those of control mice, CD4(+) T cells and not CD8(+) T cells from zetaKO mice were polarized into IFN-gamma-producing cells. Some of these IFN-gamma-producing cells could also secrete IL-10. Interestingly, zetaKO mouse T cells produced IFN-gamma even after they were cultured in a Th2 condition. Our studies to determine the molecular mechanisms underlying the polarized IFN-gamma production revealed that the expression level of STAT4 and T-bet were up-regulated in freshly isolated T cells from zetaKO mice. Further studies showed that noncultured zetaKO mice CD4(+) T cells and thymocytes bore a unique memory cell-like CD44(high), CD62L(low/neg) phenotype. Altogether, these results suggest that, in the absence of the zeta-chain, CD4(+) T cells develop as polarized IFN-gamma-producing cells that bear a memory cell-like phenotype. The zeta-chain-bearing T cells may produce a large amount of IFN-gamma only after they are cultured in a condition favoring Th1 cell differentiation. This study may provide important implications for the down-regulation of zeta-chain in T cells of patients bearing a variety of tumors, chronic inflammatory and infectious diseases.
Krymskaya
Ludmila
L
Division of Immunology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
Lee
Wen-Hui
WH
Zhong
Lingwen
L
Liu
Chih-Pin
CP
D000818:Animals; D017252:CD3 Complex / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D016764:Cell Polarity / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D007156:Immunologic Memory / Q000235:genetics / Q000276:immunology; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D021122:Protein Subunits / Q000172:deficiency* / Q000235:genetics; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050797:STAT4 Transcription Factor; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D000098815:T-bet Transcription Factor
D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins; D021122:Protein Subunits; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D016753:Interleukin-10; D007371:Interferon-gamma