Asthma: T-bet – A Master Controller?

Department of Allergy, National Heart and Lung Institute, and Leukocyte Biology, Biomedical Sciences Division, Faculty of Medicine, Imperial College, London SW7 2AZ, UK. ku.ca.ci@nosnibor.s.d

Abstract

The transcription factors T-bet and GATA3 are important reciprocal determinants of Th1 and Th2 T helper cell differentiation. Recent evidence suggests that these factors may affect airway immunopathology in asthma.

Abstract

Asthma remains one of the commonest chronic inflammatory diseases and has a major impact on the life of sufferers. It is associated with allergy mediated by IgE antibodies, eosinophilic airway inflammation and remodelling including collagen deposition beneath the epithelial basement membrane, mucus secretion and increased airway smooth muscle. These changes are thought to contribute to both the episodic airway narrowing that defines the condition and to airway hyperresponsiveness – an increased tendency to narrow the airways to irritant stimuli [1]. T helper cells are divided into subsets: Th1, producing predominantly interferon γ (IFNγ), and Th2 producing interleukin-4 (IL-4) and IL-5 but not IFNγ. IL-4 switches B cells towards IgE synthesis and IL-5 is an eosinophil survival and development factor [1,2]. Evidence is accumulating to support the view that the interplay between these T helper cell subsets is important in asthma. Recent studies have shown that Th2-type cytokines are produced by airway T cells in human asthma, and that allergen-reactive Th2 cells can be isolated from the airway of allergic asthmatics [1].

Th1 and Th2 cells develop from naïve T cells during an immune response, and largely determine the nature of that response through the profile of cytokines they secrete. This process involves a complex pattern of interacting cytokines, transcription factors and signalling pathways [2]. Szabo et al. [3] defined one such transcription factor which they termed T-bet (T box expressed in T cells) which not only induced an IFNγ-producing Th1 phenotype, but also repressed IL-4 and IL-5 production from differentiated Th2 cells. In a recent paper [4], these workers go on to show evidence for decreased numbers of CD4^{T cells expressing T-bet in the airway of human asthma patients relative to control subjects. Moreover, deletion of the T-bet gene in mice resulted in airway eosinophilia, Th2 cytokine production, airway hyper-responsiveness and changes of airway remodelling in the absence of allergen sensitisation and inhaled challenge [}4]. How do these findings relate to other published work in terms of Th1 and Th2 development and how are they relevant to our understanding of asthma?

References

1. Robinson DSTh-2 cytokines in allergic disease. Br. Med. Bull. 2000;56:956–968.[PubMed][Google Scholar]
2. O’Garra ACommit ye helpers. Nature. 2000;404:719–720.[PubMed][Google Scholar]
3. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LHA novel transcription factor, T-bet, directs Th1 lineage commitment. Cell. 2000;100:655–669.[PubMed][Google Scholar]
4. Finotto S, Neurath MF, Glickman JN, Qin S, Lehr HA, Green FH, Ackerman K, Haley K, Galle PR, Szabo SJ, et al Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet. Science. 2002;295:336–338.[PubMed][Google Scholar]
5. Grogan JL, Mohrs M, Harmon B, Lacy DA, Sedat JW, Locksley RMEarly transcription and silencing of cytokine genes underlie polarization of T helper cell subsets. Immunity. 2001;14:205–215.[PubMed][Google Scholar]
6. Dong C, Flavell RAControl of T helper cell differentiation - in search of master genes. Sci STKE. PE1. 2000[PubMed][Google Scholar]
7. Ouyang W, Ranganath SH, Weindel K, Bhattacharya D, Murphy TL, Sha WC, Murphy KMInhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. Immunity. 1998;9:745–755.[PubMed][Google Scholar]
8. Ferber IA, Lee HJ, Zonin F, Heath V, Mui A, Arai N, O’Garra AGATA-3 significantly downregulates IFN-gamma production from developing Th1 cells in addition to inducing IL-4 and IL-5 levels. Clin. Immunol. 1999;91:34–44.[PubMed][Google Scholar]
9. Mullen AC, High FA, Hutchins AS, Lee HW, Villarino AV, Livingston DM, Kung AL, Cereb N, Yao TP, Yang SY, Reiner SLRole of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science. 2001;292:1907–1910.[PubMed][Google Scholar]
10. Lighvani AA, Frucht DM, Jankovic D, Yamane H, Aliberti J, Hissong BD, Nguyen BV, Gadina M, Sher A, Paul WE, O’Shea JJT-bet is rapidly induced by interferon-gamma in lymphoid and myeloid cells. Proc. Natl. Acad. Sci. U.S.A. 2001;98:15137–15142.[Google Scholar]
11. Szabo SJ, Sullivan BM, Stemmann C, Satoskar AR, Sleckman BP, Glimcher LHDistinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells. Science. 2002;295:338–342.[PubMed][Google Scholar]
12. Nawijn MC, Dingjan GM, Ferreira R, Lambrecht BN, Karis A, Grosveld F, Savelkoul H, Hendriks RWEnforced expression of GATA-3 in transgenic mice inhibits Th1 differentiation and induces the formation of a T1/ST2-expressing Th2-committed T cell compartment in vivo. J. Immunol. 2001;167:724–732.[PubMed][Google Scholar]
13. Barat FJ, Cua DJ, Boonstra A, Richards DF, Crain C, Savelkoul HF, de Waal-Malefyt R, Coffman RL, Hawrylowicz CM, O’Garra A. In vitro generation of interleukin-10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type-1 (Th1) and Th2-inducing cytokines. J. Exp. Med. 2002;195:603–616.
14. Hogan SP, Matthaei KI, Young JM, Koskinen A, Young IG, Foster PSA novel T cell-regulated mechanism modulating allergen-induced airways hyperreactivity in BALB/c mice independently of IL-4 and IL-5. J. Immunol. 1998;161:1501–1509.[PubMed][Google Scholar]
15. McMillan SJ, Bishop B, Townsend MJ, McKenzie AN, Lloyd CMThe absence of interleukin 9 does not affect the development of allergen-induced pulmonary inflammation nor airway hyperreactivity. J. Exp. Med. 2002;195:51–57.[Google Scholar]
16. Leckie MJ, ten Brinke A, Khan J, Diamant Z, O’Connor BJ, Walls CM, Mathur AK, Cowley HC, Chung KF, Djukanovic R, et al Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness and the late asthmatic response. Lancet. 2000;356:2144–2148.[PubMed][Google Scholar]
17. Borish LC, Nelson HS, Corren J, Bensch G, Busse WW, Whitmore JB, Agosti JM, IL-4R Asthma Study Group Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J. Allergy Clin. Immunol. 2001;107:963–970.[PubMed]
18. Varga EM, Wachholz P, Nouri-Aria KT, Verhoef A, Corrigan CJ, Till SJ, Durham SRT cells from human allergen-induced late asthmatic responses express IL-12 receptor beta 2 subunit mRNA and respond to IL-12 in vitro. J. Immunol. 2000;165:2877–2885.[PubMed][Google Scholar]
19. Bryan SA, O’Connor BJ, Matti S, Leckie MJ, Kanabar V, Khan J, Warrington SJ, Renzetti L, Rames A, Bock JA, et al Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness and the late asthmatic response. Lancet. 2000;356:2149–2153.[PubMed][Google Scholar]
20. Lloyd CM, Gonzalo J-A, Coyle AJ, Gutierrez-Ramos J-CMouse models of allergic airway disease. Adv. Immunol. 2001;77:263–295.[PubMed][Google Scholar]