Trends in Immunology
ReviewNeonatal immunity: faulty T-helpers and the shortcomings of dendritic cells
Introduction
Landmark experiments by Sir Peter Medawar's group in the 1950s demonstrated that neonatal exposure to antigen (Ag) leads to a lack of responsiveness to the same Ag during a later encounter [1]. Deletion or inactivation of T cells was believed to be the underlying mechanism for such unresponsiveness [2]. Since that time, the neonatal period has been viewed as a window of opportunity for inducing unresponsiveness to specific Ag. By analogy to T cell tolerance to self Ag (Box 1), this neonatally induced unresponsiveness has been referred to as neonatal tolerance [3]. This interpretation fits well with the known susceptibility of newborns to microbial infection [4], however, it is insufficient to explain the vulnerability of infants and children to immune-mediated allergic reactions [5]. A turning point in immunology came about in the 1980s when it was recognized that T cells could be classified into subsets based on cytokine production and associated effector function [6]. T helper (Th)1 cells produce mostly interferon γ (IFNγ), an inflammatory cytokine important in responses against microbial infections, while Th2 cells secrete interleukin (IL)-4 and IL-13, which participate in immunity against parasites but also play major roles in allergic reactions. Shortly thereafter, it was reported that the newborn is indeed capable of raising an immune response 7, 8, however, the Th component of this response manifests a strong bias toward Th2 function 9, 10, 11, 12, 13, 14. Th2 cells do not elicit the usual inflammatory reactions associated with Th1 cells but nevertheless constitute responsiveness, therefore, the dogma of neonatal tolerance shifted to one of neonatal immunity (Box 2). Although unbalanced Th1:Th2 responses explain the susceptibility of the newborn to infections and allergic reactions, they raise the intriguing question as to how such a shift comes about in the first place, particularly because potent neonatal Th1 responses can develop under specific circumstances, including infection with particular microbes 8, 9, 15, 16, 17, 18, 19. In fact, a great deal of interest has been devoted recently towards defining regimens that can promote neonatal Th1 immunity 20, 21, 22. The current understanding of neonatal immunity suggests that delayed developmental maturation of accessory cells as well as T cell intrinsic epigenetic factors play major roles in the asymmetrical Th1:Th2 immunity in the newborn 23, 24, 25.
Section snippets
Primary neonatal responses comprise both Th1 and Th2 responses
The size limitations associated with murine neonates restricted the initial studies to analysis of secondary responses that arise upon re-challenge with Ag during adult life. The lymph nodes, which are the usual sites of interest for investigation of immune responses, were found initially to be unresponsive in adult mice that had been primed with Ag neonatally, which led to the belief that T-cell deletion/inactivation is the chief mechanism for the lack of adult secondary responses (Figure 1).
Neonatal Th1 immunity: imprinted attributes and the inability to withstand re-challenge with Ag
The fact that neonatal primary responses are comprised of both Th1 and Th2 cells, but that the secondary responses are biased towards Th2 cells, raises intriguing questions as to the fate of the primary Th1 cells, and the mechanism that underlies their unresponsiveness during recall with Ag 23, 25. From a practical point of view, the diminished ability of the neonate to produce Th1 responses imparts vulnerability to microbial infections, and the bias towards Th2 cells confers susceptibility to
Neonatal Th2 immunity: developmental-specific epigenetic marks facilitate Th2 function
Murine neonatal CD4+ lymph node cells produce high levels of IL-4 and IL-13 within 24 h of activation [24]. This rapid Th2 cytokine production is independent of cell cycle entry. In striking contrast, adult CD4+ T cells do not secrete substantial levels of Th2 cytokines until at least 3 days of Th2 differentiation, and only after extensive proliferation. This distinction raises the question as to the mechanism that underlies the capacity of neonates to produce rapidly Th2 cytokines. In adults, a
Sluggish maturity of accessory cells compromises neonatal Th1 immunity
The primary line of defense against microbes includes, among other mechanisms, the capture and destruction of pathogens by cells of the innate immune system. During this process, fragments of microbial constituents bind to MHC molecules and the complexes are displayed on the surface of the accessory cells. Persistent display of the complexes alerts the lymphocytes of the adaptive immune system to develop a comprehensive, robust and durable immunity against microbes. Thus, the accessory cells
Conclusions
The neonatal model illustrated in Figure 6 highlights the points that we believe control the Th2 bias of murine neonatal immunity. As a result of delayed maturation of DCs, the newborn possesses a minimal number of the Ag-presenting, IL-12-producing CD8α+CD4− subset. Consequently, very little IL-12 is available to oppose upregulation of IL-13Rα1 on primary Th1 cells and the readiness of the Th2 locus for prompt differentiation of Th2 cells. Re-challenge with Ag triggers Th2 cells to produce
Acknowledgements
This work was supported by grants RO1AI48541and R21AI062796 from the National Institutes of Health (NIH) (to H. Z.) and by the J. Lavenia Edwards Chair endowment (to H.Z.). C.M.H. was supported by training grant GM008396 from the National Institute of General Medical Sciences. B.A. was supported by grant R01AI44923 from the NIH.
References (54)
Development of allergen-specific T-cell memory in atopic and normal children
Lancet
(1999)IL-4 utilizes an alternative receptor to drive apoptosis of Th1 cells and skews neonatal immunity toward Th2
Immunity
(2004)Neonatal and early life vaccinology
Vaccine
(2001)T helper cell differentiation: regulation by cis elements and epigenetics
Immunity
(2006)The human IL-13 locus in neonatal CD4+ T cells is refractory to the acquisition of a repressive chromatin architecture
J. Biol. Chem.
(2007)Upon TLR9 signaling, CD5+ B cells control the IL-12-dependent Th1-priming capacity of neonatal DCs
Immunity
(2005)Neonatal induction of myelin-specific Th1/Th17 immunity does not result in experimental autoimmune encephalomyelitis and can protect against the disease in adulthood
J. Neuroimmunol.
(2007)Murine neonates develop vigorous in vivo cytotoxic and Th1/Th2 responses upon exposure to low doses of NIMA-like alloantigens
Blood
(2008)Actively acquired tolerance of foreign cells
Nature
(1953)Neonatal T cell tolerance to minimal immunogenic peptides is caused by clonal inactivation
Nature
(1986)