The role of the Th1 transcription factor T-bet in a mouse model of immune-mediated bone-marrow failure.
The transcription factor T-bet is a key regulator of type 1 immune responses. We examined the role of T-bet in an animal model of immune-mediated bone marrow (BM) failure using mice carrying a germline T-bet gene deletion (T-bet(-/-)). In comparison with normal C57BL6 (B6) control mice, T-bet(-/-) mice had normal cellular composition in lymphohematopoietic tissues, but T-bet(-/-) lymphocytes were functionally defective. Infusion of 5 x 10(6) T-bet(-/-) lymph node (LN) cells into sublethally irradiated, major histocompatibility complex-mismatched CByB6F1 (F1) recipients failed to induce the severe marrow hypoplasia and fatal pancytopenia that is produced by injection of similar numbers of B6 LN cells. Increasing T-bet(-/-) LN-cell dose to 10 to 23 x 10(6) per recipient led to only mild hematopoietic deficiency. Recipients of T-bet(-/-) LN cells had no expansion in T cells or interferon-gamma-producing T cells but showed a significant increase in Lin(-)Sca1(+)CD117(+)CD34(-) BM cells. Plasma transforming growth factor-beta and interleukin-17 concentrations were increased in T-bet(-/-) LN-cell recipients, possibly a compensatory up-regulation of the Th17 immune response. Continuous infusion of interferon-gamma resulted in hematopoietic suppression but did not cause T-bet(-/-) LN-cell expansion or BM destruction. Our data provided fresh evidence demonstrating a critical role of T-bet in immune-mediated BM failure.
Tang
Yong
Y
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Desierto
Marie J
MJ
Chen
Jichun
J
Young
Neal S
NS
D000818:Animals; D001772:Blood Cell Count; D001855:Bone Marrow Diseases / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology; D007154:Immune System Diseases / Q000150:complications / Q000235:genetics*; D007371:Interferon-gamma / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D000098815:T-bet Transcription Factor
D016207:Cytokines; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma