College of Medicine ; University of Arizona
Complex lung diseases, such as asthma, are characterized by Th2-dependent allergic inflammation, and result from intricate pathogenetic mechanisms strongly influenced by genetic factors, often in combination with the environment (1). Immunological events in early life - particularly, unbalanced T helper responses - are likely to play an essential role in shaping allergic inflammation in adults. Human neonatal T cells are deficient in their ability to mount Th1 responses, a feature dependent on epigenetic programs intrinsic to immune cells. Among Th2 cytokines, IL-4 and IL-5 are also drastically reduced in neonates. IL-13, on the other hand, is readily and vigorously expressed upon T cell activation, even in the absence of Th2 polarizing stimuli. The molecular mechanisms responsible for the unique propensity of neonatal CD4+ T cells to express IL-13, while the other Th2 cytokine genes remain relatively silent, are unknown but deserve elucidation, because IL-13 plays a critical role as an effector molecule of Th2-mediated inflammation, and robust correlations exist between IL-13 expression in early life and subsequent susceptibility to atopy (2). We recently analyzed the patterns of DNase I hypersensitivity and CpG methylation across the IL-13 locus in human neonatal CD4+ T cells, naive or differentiated in vitro under Th1 or Th2 polarizing conditions. We showed that the IL-13 chromatin undergoes extensive remodeling during differentiation into a polarized T helper effector phenotype. Surprisingly, overall similar patterns of chromatin accessibility and methylation were observed in Th2 and Th1 cell populations, even though IL-13 was not expressed by Th1 cells. Substantial differences in accessibility were limited to the proximal promoter, where a strong DNase I HS site was generated selectively in Th2 cells (3). Our results indicate that the proximal promoter may act as a gatekeeper of IL-13 transcription in neonatal CD4+ T cells, and suggest the IL-13 locus is refractory to the acquisition of a repressive chromatin structure, providing a potential mechanism for the propensity of neonatal T cells to express IL-13. The potential evolutionary implications of this propensity will be discussed. (Supported by NIH grants HL66391 and AI057957)
Vercelli, D. Genetics, epigenetics and the environment: Switching, buffering, releasing. J. Allergy Clin. Immunol. 113: 381-386, 2004.
Lange, J., G. Ngoumou, S. Berkenheide, M. Moseler, J. Mattes, J. Kuehr, and M. V. Kopp. High interleukin-13 production by phytohaemagglutinin- and Der p 1-stimulated cord blood mononuclear cells is associated with the subsequent development of atopic dermatitis at the age of 3 years. Clin. Exp. Allergy 33: 1537-1543, 2003.
Webster, R. B., Y. Rodriguez, W. T. Klimecki, and D. Vercelli. 2005. Extended accessibility at the IL-13 locus correlates with the propensity of human neonatal CD4+ T cells to express IL-13. (submitted for publication).