Portal de Periódicos da CAPES

Neonatal T Cell Function

2005; Lippincott Williams & Wilkins; Volume: 40; Issue: Supplement 1 Linguagem: Inglês

10.1097/00005176-200504001-00004

1536-4801

Becky Adkins,

Immune Response and Inflammation

Over the past decade, great strides have been made in our understanding of T cell function in neonates. An important key for achieving this heightened understanding is that the experimental approaches have moved beyond in vitro polyclonal activation protocols to the study of the in vivo development of antigen-specific responses. Using these approaches, a wealth of new information has been generated both from murine neonatal models and from studies on human infants and children. Although the results often seem confusing or inconsistent, important new patterns are emerging. Moreover, it is becoming increasingly apparent that there are many shared characteristics between the developing immune systems of mice and humans. RELATIVE MATURITY OF THE DEVELOPING IMMUNE SYSTEMS IN MICE AND HUMANS By several measures, newborn (≤1 day old) mice are immunologically less mature than newborn humans. As one example, the enzyme TdT is developmentally regulated in both mice and humans but the timing of mature expression differs. In mice, TdT expression is not fully turned on until 4 to 7 days post birth whereas TdT expression reaches mature levels around the beginning of the second trimester in human gestation. Based on antibody responses to vaccine antigens and colonization of secondary lymphoid organs, 7-day-old mice are more similar to newborn children. In the mouse, immunologic maturity is then acquired gradually over the next 3 to 5 weeks of life. COMMONLY OBSERVED REDUCTIONS IN IMMUNE FUNCTION IN NEWBORNS Vaccination of human or mouse babies leads to antibody responses that are qualitatively and quantitatively diminished, compared to adult responses. The newborn antibody responses are often decreased in initial quantity, poorly sustained, and/or have reduced affinity/avidity. As is well known, newborns and young children are also exquisitely sensitive to infectious agents. Lastly, at least in the mouse, the newborn period of life is thought to be a window of time in which tolerance to exogenously introduced antigens can be achieved with ease. CD4+ T HELPER SUBSETS Immune responses to vaccines or infectious agents as well as the induction of tolerance often require the function of T helper cells. There are two major types of Th cells. Th1 cells are important for cell-mediated immunity and a potent Th1 response is often associated with the development of CD8+ CTL activity. Th1 cells secrete proinflammatory products with the hallmark Th1 cytokine being γIFN. Th2 cells are critical for humoral immunity. The products of Th2 cells are anti-inflammatory and include the cytokines IL-4, IL-5, IL-10, and IL-13. STANDARD IMMUNIZATION CONDITIONS LEAD TO A Th2 IMMUNE DEVIATION IN MURINE NEWBORNS Immunization of murine neonates with standard vaccine-like antigens (e.g., with alum adjuvant) leads to Th2-biased secondary responses when the animals are re-immunized as adults. Thus, exposure to antigen in the neonatal period leads to an "imprinting" of Th2 dominance that is maintained into adulthood. This Th2 bias has important physiological ramifications for several reasons. First, Th2 cytokines lead to the preferential production of the Th2-associated isotype IgG1. Thus, the net effector functions associated with different Ig isotypes will be different in animals immunized as neonates vs adults. Second, Th2 function has been shown to be critical for the induction and maintenance of tolerance to alloantigens in murine newborns. Third, this Th2 dominance has important regulatory effects since Th2 skewing in response to one antigen has been shown to deviate the responses to unrelated antigens to the Th2 lineage. Last, because Th1 activity is relatively diminished, Th1-mediated and the often-associated CD8+ CTL-mediated protective immunity are severely compromised. In murine neonates, Th2-biased secondary responses may arise by some combination of: (a) dysregulation of the normal process of curtailment of a primary Th2 response; (b) the deficient development of Th1 memory effector function; and (c) the generation of Th2 dominant primary responses. HUMAN CORRELATE TO MURINE NEWBORN Th2 BIAS Exposure to common environmental allergens in utero results universally in Th2-biased responses in human newborns. Whether an individual child becomes allergic is defined over the next couple of years of life with non-allergic children downregulating Th2 function and upregulating Th1 function. Allergic individuals, on the other hand, consolidate their Th2 activity and fail to normally upregulate Th1 activity. VARYING THE CONDITIONS OF ANTIGEN EXPOSURE LEADS TO PARTIALLY OR FULLY MATURE Th RESPONSES IN MURINE NEWBORNS: PLASTICITY OF NEONATAL RESPONSIVENESS After the initial descriptions of Th2 bias in murine neonates, many investigators began to expose newborns to antigens under a variety of conditions known to promote strong Th1 responses in adults. These combined studies have shown that neonatal responses are quite variable, ranging from the standard Th2 dominance to Th1/Th2 hyporesponsiveness to partially mature Th1 responses and, finally, to fully mature Th1 and CTL responses (Fig. 1). These results have led to two important conclusions. First, murine neonates are clearly competent to develop adult-like Th1/CTL function when the conditions are appropriately manipulated. Second, neonatal responses are remarkably plastic and highly dependent on the conditions of antigen exposure.FIG. 1: Plasticity of T cell responses in early life in both humans and mice. Infection or exposure to antigens in fetal or neonatal life often leads to T cell responses which are qualitatively or quantitatively different from adult responses. Each box in the figure represents responses observed under different conditions of antigen exposure. Boxes above the arrow refer to responses to the antigen(s) listed above the arrow; boxes below the arrow refer to responses to the antigen(s) listed below the arrow. The possible responses are varied and include Th2-dominant responses (large circles), diminished production of both Th1 and Th2 cytokines (small circles), diminished Th1 or CTL responses (small circles), or generalized hyporesponsiveness. However, some conditions of antigen exposure lead to mature Th1 and/or CTL responses (large circles).EMERGING FINDINGS ON HUMAN, FETAL, NEONATAL, AND JUVENILE RESPONSES: EARLY HUMAN RESPONSES ALSO APPEAR TO BE QUITE PLASTIC In parts of the world where various infectious agents are endemic, researchers are studying the responses of infants and children exposed to infectious agents under a variety of conditions. These conditions include congenital infection, in utero antigen exposure in the absence of infection, perinatal exposure to infectious agents and initial infection during childhood. Moreover, the Th and CTL responses developing to vaccine antigens are now under careful scrutiny. Results to date indicate that the developing human immune system shares a plasticity of responsiveness with that of murine neonates. Various responses with the entire range from complete hyporesponsiveness to mature Th1/CTL responses have been observed (Fig. 1). Thus, the mouse, human infants, newborns and children are apparently competent to mount mature Th responses. Although it is more difficult to determine in humans, the plasticity of response also seen in human newborns may also be due to the conditions of antigen exposure. ADVANTAGES OF PLASTICITY OF IMMUNE RESPONSIVENESS FROM THE NEWBORN'S PERSPECTIVE Why are responses so plastic in early life? If one considers survival of the individual and, hence, survival of the species, it makes a good deal of sense. The newborn is literally bombarded with a huge array of novel environmental antigens. Tolerance or non-responsiveness to most of these antigens must first be established in neonatal life. It is also in the neonatal period of life that tolerance to peripheral tissue antigens must first be established. In addition to tolerizing mechanisms, the newborn must also have at its disposal the ability to activate a protective immune response against newly encountered infectious agents. Thus, given the multiple tasks that must be performed in the newborn, plasticity in early life would appear to be an advantage. T REGULATORY CELLS (Treg) It is clear the regulatory T cell function is an important player in many immune responses. Numerous types of Treg have been described, including CD4+25+ cells, NK T cells, Th3 cells, Tr1 cells, CD8+ cells and possibly of great importance for IBD, CD4+8αα cells. In some cases, Treg have been described to downregulate both Th1 and Th2 function and thus stand in a key position to determine the net immune response. The mechanisms of action of Treg remain somewhat controversial but may include the inhibitory cytokines IL-10 and TGFβ and inhibitory cell contact dependent signals. Treg have been strongly implicated in numerous mouse models of autoimmune disease and allergy. THE IMPORTANCE OF T REGULATORY CELLS IN NEWBORNS? In the mouse, it is clear that T regulatory (Treg) cells are active early in life. For example, neonatal thymectomy leads to organ specific autoimmunity. This is apparently due to the lack of sufficient numbers of thymically-derived Treg since the injection of Treg into neonatally thymectomized animals prevents the development of autoimmune disease. As another example, in the mouse model for juvenile onset diabetes (non-obese diabetes, NOD), there are multiple defects in Treg function and the introduction of normal Treg can downmodulate disease. In humans, there is an emerging picture of Treg function in neonates and juveniles. Cells with CD4+25+ Treg phenotype and functional activity are present in cord blood. Interestingly, in the X-linked disease IPEX syndrome, there is the early development of multiorgan autoimmune diseases, including IBD. Recent work indicates that the disease may be due to the failure of development of the CD4+25+ Treg population. In juvenile onset diabetes, Treg have been reported to be reduced in number (CD4+25+ and NK T cells) and function (NK T cells). Lastly, the development of Treg function is associated with success in specific immuno-therapy of allergies and in the remission of juvenile idiophathic arthritis (Fig. 1). Key Questions 1) How do the conditions of antigen exposure (antigen dose, inflammation, infectious agents or antigens) contribute to the generation of the plasticity of the human neonatal response? 2) What is the role of the Treg network in human pediatric autoimmune disease, allergy and infectious disease? 3) What are the molecular regulators of the unique responsiveness during neonatal life? 4) Can we safely and effectively harness the plasticity of the neonatal response to treat or prevent disease in the pediatric population?