Sensitization or Tolerance?
T cell regulatory mechanisms in tolerance to inhaled allergens
Patrick G. Holt DSc, FRCPath, FAA
Telethon Institute for Child Health Research
The immunological consequences of allergen exposure range from induction of classical immunological tolerance via T cell anergy/deletion, to expression of allergy-associated Th2 mediated inflammation, or cognate immunity (as evidenced by the presence of Th1 polarised or Th2 polarised memory cells in blood) in the virtual absence of discernible symptomatology. Distinct T cell regulatory mechanisms are associated with each of these manifestations of allergen responsiveness. This presentation focuses on new information relevant to our understanding of the T cell priming process which precedes these various expressions of allergen-specific immunity.
(i) Nature of allergen-specific T cell responses in neonates and infants
A number of laboratories have demonstrated the presence of allergen-specific T cells in cord blood, suggesting transplacental priming of Th memory cells. Our recent studies indicate that a prominent feature of these neonatal T cell responses is large scale apoptosis, accompanied by maturation within the surviving populates of a subset of CD4+ CD25+ CTLA4+ T cells which express immunosuppressive activity in vitro analogous to T regulatory cells. These putative T regulator cells may be involved in control of initial allergen-specific Th memory generation in the early postnatal period, and/or may survive into later childhood, to function as dampeners of atopic reactions.
(ii) T cell function in the foetal compartment
We have shown previously that genetic risk for atopy is associated with attenuation of both Th1 and Th2 functions during infancy. Recent results indicate expression of a comparable hyporesponsive T cell phenotype in utero in subjects who subsequently develop asthma/atopy in later childhood. Moreover, we demonstrate that toxic exposures in the maternal environmental (notably tobacco smoke exposure) can further attenuate T cell function in the foetus, thus heightening risk for subsequent atopic sensitisation after birth.
(iii) Regulation of Th1 function in early life
Capacity to produce the cytokine IFN develops relatively slowly postnatally. Our recent studies have focused upon mechanism(s) of control of IFN gene transcription during early life. We demonstrate that transcription is regulated via control of the level of methylation at CpG sites within the proximal promoter of the IFN gene. In naive CD4+ T cells from neonates the levels of IFN promoter methylation are significantly higher than in comparable naive cells from adults, reflecting the lower IFN response capacity in early life. Studies are in progress to determine whether variations in the efficiency of this regulatory mechanism during early childhood are associated with variations in risk for allergic disease.
- Rowe J, Macaubas C, Monger T, Holt BJ, Harvey J, Poolman JT, Loh R, Sly PD and Holt PG. Heterogeneity in diphtheria-tetanus-acellular vaccine-specific cellular immunity during infancy: relationship to variations in the kinetics of postnatal maturation of systemic Th1 function. J Infect Dis 2001, 184:80-8.
- Macaubas C, Lee PT, Smallacombe TB, Holt BJ, Wee C, Sly PD and Holt PG. Reciprocal patterns of allergen induced GATA 3 expression in peripheral blood mononuclear cells from atopics versus non atopics. Clin Exp Allergy 2002, 32:97 106.
- White GP, Watt PM, Holt BJ and Holt PG. Differential patterns of methylation of the IFN promoter at CpG and non CpG sites underlie differences in IFN gene expression between human neonatal and adult CD450RO T cells. J Immunol 2002, 168:2820 7.
- Holt PG and Sly PD. Interactions between RSV infection, asthma and atopy: unravelling the complexities. J Exp Med 2002, 196:1271-1275.
- Morahan G, Huang D, Wu M, Holt BJ, White GP, Kendall G, Sly PD, Holt PG. Association of IL12B promoter polymorphism with severity of atopic and non-atopic asthma in children. Lancet 2002, 360:455 459.
Patrick G. Holt DSc, FRCPath, FAA
Patrick Holt is the Deputy Director of the Telethon Institute for Child Health Research in Perth, and Head of the Institute's Division of Cell Biology. He is additionally a Senior Principal Research Fellow of the National Health & Medical Research Council of Australia, and Professor in the Centre for Child Health Research, University of Western Australia. He leads a group of 25 scientists in research into the aetiology and pathogenesis of immunologically mediated inflammatory diseases, in particular atopic asthma, with a major emphasis on paediatrics and the development of early disease intervention strategies.