Reviews and feature article: T-box 21 transcription factor is responsible for distorted TH2 differentiation in human peripheral CD4 T cells

• Published in: Journal of allergy and clinical immunology Vol. 123; no. 4; pp. 813 - 823.e3
• Main Authors: Kaminuma, Osamu, Kitamura, Fujiko, Miyatake, Shoichiro, Yamaoka, Kazuko, Miyoshi, Hiroyuki, Inokuma, Shigeko, Tatsumi, Hideki, Nemoto, Soichi, Kitamura, Noriko, Mori, Akio, Hiroi, Takachika
• Format: Journal Article
• Language: English
• Published: 01.04.2009
• ISSN: 0091-6749
• DOI: 10.1016/j.jaci.2009.01.055

Background Regardless of TH1/TH2 theory, CD4+ T cells of patients with allergic asthma, a typical TH2 disease, and those of healthy subjects expressed equivalent levels of IFN- gamma , even though TH2 cytokines were significantly upregulated in asthmatic patients. Objective The mechanisms underlying distorted TH2 cell polarization in human T cells were elucidated. Methods Cytokine-producing activity and the expression of TH1/TH2-specific transcription factors in naive, TH1/TH2, 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 TH1/TH2 differentiation were further investigated. Results TH2 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 TH2-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 TH1/TH2 balance. Conclusion 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 TH2-related diseases.