Impaired secretion of interleukin-4 and interleukin-13 by allergen-specific T cells correlates with defective nuclear expression of NF-AT2 and jun B: relevance to immunotherapy.
BACKGROUND
Allergen immunotherapy (IT) is a successful treatment associated with decreased Th2 cytokine production by allergen-specific T cells. We have previously demonstrated (Faith et al., J Immunol 1997; 159:53-57) that inhibition of Th2 cytokine production in vitro correlates with impaired tyrosine kinase activity through the TCR. The transcription factor complex, nuclear factor of activated T cells (NF-AT), which regulates Th2 cytokine production is controlled by the activity of tyrosine kinases.


OBJECTIVE
To address whether decreased Th2 cytokine production by allergen-specific CD4+ T cells following IT is correlated with altered translocation and nuclear expression of the NF-AT family member, NF-AT2, and the activator protein 1 (AP1) component of NF-AT, jun B.


METHODS
T cell lines specific for insect venom phospholipase A2 (PLA) were derived from patients prior to and during conventional venom IT. Nuclear expressions of NF-AT and jun B were assessed following stimulation through the TCR. Th1 and Th2 cytokine and IL-10 production by insect venom-specific T cells were also determined. Results were compared with a well-established model system in which anergy was induced in cloned, allergen-specific Th2 cells.


RESULTS
Impaired translocation and decreased expression of NF-AT2 and jun B were detected in PLA-specific T cell lines derived from bee venom-allergic individuals following 16 weeks treatment compared to pre-treatment. These results correlated with significantly reduced production of IL-4 and IL-13 and significantly increased production of IFN-gamma and IL-10 by PLA-specific T cells. Impaired IL-4 and IL-13 production also correlated with defective nuclear expression of NF-AT2/jun B in cloned, anergic allergen-specific Th2 cells.


CONCLUSIONS
These results suggested that optimal production of IL-4 and IL-13 by allergen-specific T cells is dependent on the nuclear expression of NF-AT2 and jun B. Thus, specific inhibition of NF-AT2/jun B might be an option in novel and improved forms of allergen IT.
Faith
A
A
Department of Respiratory Medicine and Allergy, The Guy's, King's College and St Thomas' Hospitals School of Medicine, London, UK. alex.faith@kcl.ac.uk
Richards
D F
DF
Verhoef
A
A
Lamb
J R
JR
Lee
T H
TH
Hawrylowicz
C M
CM
D000485:Allergens / Q000276:immunology; D001514:Bee Venoms / Q000276:immunology; D002460:Cell Line; D002467:Cell Nucleus / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis; D018793:Interleukin-13 / Q000096:biosynthesis* / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000276:immunology; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010741:Phospholipases A / Q000276:immunology; D054467:Phospholipases A2; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics; D014862:Wasp Venoms / Q000276:immunology
D000485:Allergens; D001514:Bee Venoms; D004268:DNA-Binding Proteins; D018793:Interleukin-13; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D016755:Proto-Oncogene Proteins c-jun; D011948:Receptors, Antigen, T-Cell; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014862:Wasp Venoms; D015847:Interleukin-4; D007371:Interferon-gamma; D010741:Phospholipases A; D054467:Phospholipases A2