T-box 21 transcription factor is responsible for distorted T(H)2 differentiation in human peripheral CD4+ T cells.
BACKGROUND
Regardless of T(H)1/T(H)2 theory, CD4(+) T cells of patients with allergic asthma, a typical T(H)2 disease, and those of healthy subjects expressed equivalent levels of IFN-gamma, even though T(H)2 cytokines were significantly upregulated in asthmatic patients.


OBJECTIVE
The mechanisms underlying distorted T(H)2 cell polarization in human T cells were elucidated.


METHODS
Cytokine-producing activity and the expression of T(H)1/T(H)2-specific transcription factors in naïve, T(H)1/T(H)2, or both CD4(+) T cells derived from human peripheral and cord blood were comparatively analyzed. The mechanisms of the differential expression of T-box 21 transcription factor (T-bet) in the cells were assessed by determining the chromatin accessibility at the TBX21 gene. The functional roles of T-bet and other transcription factors in human T(H)1/T(H)2 differentiation were further investigated.


RESULTS
T(H)2 cells derived from naive CD4(+) T cells in peripheral blood but not in cord blood produced IFN-gamma. T-bet was expressed in peripheral, but not cord blood, resting naive T cells. Consistently, the accessibility at the proximal TBX21 gene promoter in peripheral naive T cells was higher than that in cord blood naive T cells. IFN-gamma-producing activity was induced in T(H)2-differentiated cord blood T cells by means of ectopic expression of T-bet. In addition, a reduction of T-bet in peripheral T cells suppressed IFN-gamma production. T-bet not only upregulated IFN-gamma but also downregulated IL-4 and IL-13 gene transcription, independently of the modification of T(H)1/T(H)2 balance.


CONCLUSIONS
The expression of T-bet at a naive stage is crucial for the development of IFN-gamma-producing T cells in human peripheral blood, even in T(H)2-related diseases.
Department of Allergy and Immunology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Osamu
O
Kaminuma
Fujiko
F
Kitamura
Shoichiro
S
Miyatake
Kazuko
K
Yamaoka
Hiroyuki
H
Miyoshi
Shigeko
S
Inokuma
Hideki
H
Tatsumi
Soichi
S
Nemoto
Noriko
N
Kitamura
Akio
A
Mori
Takachika
T
Hiroi
D000328:Adult; D000368:Aged; D001249:Asthma / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D050990:GATA3 Transcription Factor / Q000502:physiology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D020825:T-Box Domain Proteins / Q000235:genetics / Q000502:physiology*; D018418:Th2 Cells / Q000166:cytology* / Q000276:immunology; D000098815:T-bet Transcription Factor
D016207:Cytokines; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma