TH2 adjuvants: Implications for food allergy
2008; Elsevier BV; Volume: 121; Issue: 6 Linguagem: Inglês
10.1016/j.jaci.2008.04.023
ISSN1097-6825
AutoresM. Cecilia Berin, Wayne G. Shreffler,
Tópico(s)Eosinophilic Esophagitis
ResumoA persistent question for immunologists studying allergic disease has been to define the characteristics of a molecule that make it allergenic. There has been substantial progress elucidating mechanisms of innate priming of TH2 immunity in the past several years. These accumulating data demonstrate that TH2 immunity is actively induced by an array of molecules, many of which were first discovered in the context of antihelminthic immune responses. Similar intrinsic or associated activities are now known to account for the TH2 immunogenicity of some allergens, and may prove to play a role for many more. In this review, we discuss what has been discovered regarding molecules that induce innate immune activation and the pathways that promote TH2-polarized immune responses generally, and specifically what role these mechanisms may play in food allergy from models of food allergy and the study of TH2 gastrointestinal adjuvants. A persistent question for immunologists studying allergic disease has been to define the characteristics of a molecule that make it allergenic. There has been substantial progress elucidating mechanisms of innate priming of TH2 immunity in the past several years. These accumulating data demonstrate that TH2 immunity is actively induced by an array of molecules, many of which were first discovered in the context of antihelminthic immune responses. Similar intrinsic or associated activities are now known to account for the TH2 immunogenicity of some allergens, and may prove to play a role for many more. In this review, we discuss what has been discovered regarding molecules that induce innate immune activation and the pathways that promote TH2-polarized immune responses generally, and specifically what role these mechanisms may play in food allergy from models of food allergy and the study of TH2 gastrointestinal adjuvants. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: June 2008. Credit may be obtained for these courses until May 31, 2010.Copyright Statement: Copyright © 2008-2010. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members:Authors: M. Cecilia Berin, PhD, and Wayne G. Shreffler, MD, PhDActivity Objectives1. To review how cytokines and dendritic cells lead to CD4+ T-cell differentiation. 2. To discuss adjuvants that promote TH2 differentiation. 3. To understand the role of TH2 immune responses and adjuvants in food allergy.Recognition of Commercial Support: This CME activity is supported by an educational grant from Merck & Co., Inc.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: Wayne G. Schreffler has received research support from the National Institute of Allergy and Infectious Diseases and the Food Allergy Initiative. M. Cecilia Berin has no signficant relationships to disclose.GlossaryCD MARKERS ON DENDRITIC CELLSDendritic cell (DC) subsets can be distinguished by the expression of surface markers. In mouse, all DCs are positive for the surface marker CD11c (an adhesion molecule). Other markers used to distinguish DC subsets in mice include CD11b, CD8α, B220, Gr-1, and others. In human beings, other surface markers are commonly used to distinguish DCs and DC subsets. The surface markers have various functions, but they are primarily used as tools in flow cytometry or by immunohistochemistry to identify DC subsets that have specialized functions.CENTRAL MEMORY T LYMPHOCYTESAfter activation of naive T cells (CD4 and CD8 T cells), differentiation can lead to the generation of memory T cells with either a central or effector memory phenotype. Effector memory cells rapidly secrete large amounts of cytokines after re-stimulation and express homing markers that make them specialized for entry into inflamed peripheral tissues. Central memory cells stay in the lymph nodes (and express the lymph node homing chemokine receptor CCR7 and the lymph node homing adhesion molecule CD62L). They are slower to become activated and secrete lower levels of cytokines, but can differentiate into effector memory T cells after reactivation.DENDRITIC CELLS (DCs)Antigen presenting cells (APCs) that capture antigen in the periphery, traffic to draining lymph nodes, and process and present antigen to T lymphocytes through major histocompatibility complex (MHC) II–T-cell receptor (TCR) interactions. DCs can respond to exogenous stimuli to upregulate costimulatory molecules and cytokine secretion that can influence the response of the responder T cell.PATTERN RECOGNITION RECEPTORS (TLRs, NODs, DECTIN, DC-SIGN)Innate recognition of microorganisms occurs through pattern recognition receptors (PRRs), of which many different types have been described. These include Toll-like receptors (TLRs), NOD1 and NOD2 (containing a nucleotide-binding oligomerization domain, which gives them their name), and a number of C-type lectin receptors such as Dectin-1 and DC-SIGN. PRRs recognize pathogen-associated molecular patterns (PAMPs), which are repeating structures common to categories of microorganisms (gram negative bacteria, gram positive bacteria, fungi, viruses). PRRs can be on the cell surface (such as TLR4 that recognizes lipopolysaccharide) or within the cell (such as NOD1 or NOD2 that recognize fragments of bacterial cell-wall proteoglycans or TLR9 that recognizes unmethylated CpG DNA). PRRs are found on a wide range of cell types, including DCs, and can promote phagocytosis of microorganisms, promote chemotaxis to sites of infections, and induce the release of effector molecules such as chemokines and cytokines. Several of the PRRs use common signaling pathways, such as the adaptor molecule MyD88 which is involved in signaling through the TLRs (except TLR3). The use of genetically modified mice with a deleted MyD88 gene (MyD88-/-) allows investigators to test the broad role of TLRs in different immune responses.PEYER PATCH (PP)Together with the mesenteric lymph node (MLN), PPs are the major immune inductive site of the gastrointestinal tract. PPs are lymphoid aggregates within the gastrointestinal mucosa, and are found throughout the small intestine and in the rectum. The epithelium overlying PPs consist of specialized cells called microfold (M) cells, that have sparse cytoplasm and microvilli and transport particulate antigens (including viruses, bacteria) to the lymphoid cells of the PP.TH1, TH2, TH17, AND REGULATORY T CELLSAfter activation by DCs, naive CD4+ T cells differentiate into cytokine-secreting cells that can be divided into categories based on their cytokine secretion. TH1 cells secrete IFN-γ, TH2 secrete IL-4 and IL-13 (and others including IL-5, IL-9, IL-10), TH17 secrete IL-17, and regulatory T cells produce IL-10 and/or TGF-β. This specialized cytokine secretion is associated with a specialization of function, such that TH1 cells promote clearance of intracellular pathogens, TH2 cells provide B cell help and promote humoral immunity, TH17 cells enhance neutrophil responses and promote clearance of extracellular bacteria, and regulatory T cells suppress the other T cell subsets to prevent excess or damaging immune responses. Purified foreign proteins vary widely in their capacity to induce an immune response. This fact has led to an effort to define the features of an antigen that make it immunogenic. In the field of allergy, this question is often posed more specifically as follows: what features of an antigen not only promote its recognition by the mammalian immune system but also specifically promote an allergic response—at least in a subset of susceptible individuals? In other words, what makes an allergen an allergen? Recognizing that features such as lack of self-homology, structural stability, and route of administration play significant roles, an important answer to that question remains: an adjuvant. Immune adjuvants are "substances and formulations that have the capacity to increase the immune response to an antigen."1Nossal G.J.V. Vaccines.in: Paul W. Fundamental immunology. 4th ed. Lippincott-Raven, Philadelphia1999: 1387-1425Google Scholar It has been recognized for many years that adjuvants promote the uptake of antigen by antigen-presenting cells (APCs)—especially dendritic cells (DCs)—and in many cases promote the activation of those APCs. These adjuvant factors include rendering antigen particulate rather than soluble, promoting slow antigen release, and, perhaps most importantly, associating with molecules that target and, either directly or indirectly, activate APCs. Since the discovery and elucidation of the role of mammalian Toll-like receptors (TLRs) beginning in the late 1990s,2Medzhitov R. Preston-Hurlburt P. Janeway Jr., C.A. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity.Nature. 1997; 388: 394-397Crossref PubMed Scopus (3024) Google Scholar many of the mechanistic details have been filled in to explain how a number of adjuvant molecules (eg, LPS, unmethylated cytosine-guanine rich nucleotide sequences [CpG], single-stranded RNA) activate innate immune cells, including DCs, to enhance adaptive immunity. TLRs, along with a growing list of other molecules (C-type lectin receptors, nucleotide binding oligomerization domain protein 1), have been termed pattern recognition receptors (PRRs) for their ability to sense pathogen-associated molecular patterns (PAMPs). Pattern recognition receptor–mediated adjuvants have been largely associated with the enhancement of TH1 (or TH17) and not TH2 immunity. More recently, several examples of TH2-promoting pathways have been described, and these are the focus of this review. Although relatively little has been shown that is directly implicated in the development of food allergy, we discuss molecules and pathways that have been shown to favor TH2 immunity in either in vitro or in vivo systems with an emphasis on non-TLR pathways, and where possible, we discuss what has been shown from murine models of food allergy and potential implications with an emphasis on the early sensitization events that are necessary for the subsequent manifestations of food allergy. Food allergy is a broad term for immune-mediated adverse reactions to food, which includes conditions that are not strongly associated with TH2 immunity (eg, gluten-sensitive enteropathy, food protein–induced enterocolitis syndrome, and so forth). However, most manifestations of food allergy, including IgE-mediated food allergy, as well as inflammatory skin or gut diseases that can be driven by food antigens, are TH2-mediated—as evidenced clinically by the production of high-affinity specific IgE, the presence of inflammation characteristic of a TH2 cytokine milieu (eg, eosinophilia, mastocytosis), and the efficacy of therapeutics that target TH2 pathways.3Chehade M. Mayer L. Oral tolerance and its relation to food hypersensitivities.J Allergy Clin Immunol. 2005; 115 (quiz 3): 3-12Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar Additional supporting evidence comes from in vitro T-cell studies and animal models of disease. The main site of exposure to food allergens is the gastrointestinal tract, although that does not necessarily preclude a role for other sites such as skin or the respiratory tract in the sensitization to food proteins.4Lack G. Fox D. Northstone K. Golding J. Factors associated with the development of peanut allergy in childhood.N Engl J Med. 2003; 348: 977-985Crossref PubMed Scopus (390) Google Scholar, 5Strid J. Hourihane J. Kimber I. Callard R. Strobel S. Epicutaneous exposure to peanut protein prevents oral tolerance and enhances allergic sensitization.Clin Exp Allergy. 2005; 35: 757-766Crossref PubMed Scopus (98) Google Scholar The main function of the gastrointestinal tract is digestion and absorption of nutrients. To facilitate that process, the intestine is composed of a very large surface area with a single layer of columnar epithelial cells forming the barrier between the external (lumen) and internal environments. Although M cells overlying Peyer patches have traditionally been thought of as the main sites of antigen entry, soluble antigens can traffic across enterocytes intact and gain access to immune cells in the lamina propria (LP),6Cornell R. Walker W.A. Isselbacher K.J. Small intestinal absorption of horseradish peroxidase: a cytochemical study.Lab Invest. 1971; 25: 42-48PubMed Google Scholar, 7Walker W.A. Cornell R. Davenport L.M. Isselbacher K.J. Macromolecular absorption: mechanism of horseradish peroxidase uptake and transport in adult and neonatal rat intestine.J Cell Biol. 1972; 54: 195-205Crossref PubMed Google Scholar, 8Warshaw A.L. Walker W.A. Cornell R. Isselbacher K.J. Small intestinal permeability to macromolecules: transmission of horseradish peroxidase into mesenteric lymph and portal blood.Lab Invest. 1971; 25: 675-684PubMed Google Scholar, 9Berin M.C. Kiliaan A.J. Yang P.C. Groot J.A. Taminiau J.A. Perdue M.H. Rapid transepithelial antigen transport in rat jejunum: impact of sensitization and the hypersensitivity reaction.Gastroenterology. 1997; 113: 856-864Abstract Full Text PDF PubMed Scopus (131) Google Scholar where they may then be transported via DCs to the draining mesenteric lymph node (MLN).10Huang F.P. Platt N. Wykes M. Major J.R. Powell T.J. Jenkins C.D. et al.A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes.J Exp Med. 2000; 191: 435-444Crossref PubMed Scopus (655) Google Scholar, 11Liu L.M. MacPherson G.G. Antigen acquisition by dendritic cells: intestinal dendritic cells acquire antigen administered orally and can prime naive T cells in vivo.J Exp Med. 1993; 177: 1299-1307Crossref PubMed Google Scholar, 12Liu L.M. MacPherson G.G. Antigen processing: cultured lymph-borne dendritic cells can process and present native protein antigens.Immunology. 1995; 84: 241-246PubMed Google Scholar Particulate antigens, in contrast, are preferentially taken up by M cells and can be presented by subepithelial dendritic cells to T cells within the Peyer patch.13Frey A. Giannasca K.T. Weltzin R. Giannasca P.J. Reggio H. Lencer W.I. et al.Role of the glycocalyx in regulating access of microparticles to apical plasma membranes of intestinal epithelial cells: implications for microbial attachment and oral vaccine targeting.J Exp Med. 1996; 184: 1045-1059Crossref PubMed Google Scholar, 14Neutra M.R. Mantis N.J. Kraehenbuhl J.P. Collaboration of epithelial cells with organized mucosal lymphoid tissues.Nat Immunol. 2001; 2: 1004-1009Crossref PubMed Scopus (287) Google Scholar Antigens delivered via the oral route normally evoke an immune response characterized as regulatory or tolerogenic, and this active regulatory response is one mechanism responsible for the phenomenon of oral tolerance (see review of oral tolerance3Chehade M. Mayer L. Oral tolerance and its relation to food hypersensitivities.J Allergy Clin Immunol. 2005; 115 (quiz 3): 3-12Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar). Although oral tolerance was initially defined experimentally in rodents by demonstrating a systemic nonresponsiveness to antigens after oral exposure, this process has also been demonstrated to occur in human beings.15Husby S. Mestecky J. Moldoveanu Z. Holland S. Elson C.O. Oral tolerance in humans: T cell but not B cell tolerance after antigen feeding.J Immunol. 1994; 152: 4663-4670PubMed Google Scholar, 16Kraus T.A. Toy L. Chan L. Childs J. Mayer L. Failure to induce oral tolerance to a soluble protein in patients with inflammatory bowel disease.Gastroenterology. 2004; 126: 1771-1778Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar Food allergy is generally thought to be a result of a defect in the generation of these normal regulatory responses, whereas outgrowing food allergy is a result of the acquisition of immune tolerance.17Karlsson M.R. Rugtveit J. Brandtzaeg P. Allergen-responsive CD4+CD25+ regulatory T cells in children who have outgrown cow's milk allergy.J Exp Med. 2004; 199: 1679-1688Crossref PubMed Scopus (262) Google Scholar Thus, it is not the presence of an immune response to food antigens that is the basis for food allergy; it is the type of immune response. Therefore, molecules with intrinsic or associated TH2-skewing adjuvant activity may play a significant role in the development of allergic sensitization to food proteins. For food allergens to initiate allergic sensitization, they must first breach the normal gut barriers, including acidity, digestion, motility, mucin layers, IgA, and the tight junctions of the enterocytes that prevent passage of macromolecules. Resistance to heat, acidity, and digestion are important characteristics common to many food allergens.18Breiteneder H. Mills E.N. Molecular properties of food allergens.J Allergy Clin Immunol. 2005; 115 (quiz 4): 14-23Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar Factors that interfere with these normal barriers to antigen penetration have been shown in some experimental systems to promote allergic sensitization. Inhibition of gastric acid (by sucralfate or by H2 receptor blockade) facilitates allergic sensitization to fish roe antigen in mice,19Untersmayr E. Scholl I. Swoboda I. Beil W.J. Forster-Waldl E. Walter F. et al.Antacid medication inhibits digestion of dietary proteins and causes food allergy: a fish allergy model in BALB/c mice.J Allergy Clin Immunol. 2003; 112: 616-623Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar although the aluminum in sucralfate has adjuvant activity when given parenterally,20Brunner R. Wallmann J. Szalai K. Karagiannis P. Kopp T. Scheiner O. et al.The impact of aluminium in acid-suppressing drugs on the immune response of BALB/c mice.Clin Exp Allergy. 2007; 37: 1566-1573Crossref PubMed Scopus (21) Google Scholar and therefore may contribute to the effect seen in the gastrointestinal tract. Psychological stress, which perturbs tight junctions of the small and large intestine and allows macromolecular passage across the epithelial barrier,21Santos J. Saunders P.R. Hanssen N.P. Yang P.C. Yates D. Groot J.A. et al.Corticotropin-releasing hormone mimics stress-induced colonic epithelial pathophysiology in the rat.Am J Physiol. 1999; 277: G391-G399PubMed Google Scholar, 22Saunders P.R. Santos J. Hanssen N.P. Yates D. Groot J.A. Perdue M.H. Physical and psychological stress in rats enhances colonic epithelial permeability via peripheral CRH.Dig Dis Sci. 2002; 47: 208-215Crossref PubMed Scopus (84) Google Scholar has also been shown to facilitate alum-induced sensitization to luminal antigens.23Yang P.C. Jury J. Soderholm J.D. Sherman P.M. McKay D.M. Perdue M.H. Chronic psychological stress in rats induces intestinal sensitization to luminal antigens.Am J Pathol. 2006; 168 (quiz 363): 104-114Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar Yamaguchi et al24Yamaguchi N. Sugita R. Miki A. Takemura N. Kawabata J. Watanabe J. et al.Gastrointestinal Candida colonisation promotes sensitisation against food antigens by affecting the mucosal barrier in mice.Gut. 2006; 55: 954-960Crossref PubMed Scopus (22) Google Scholar used gastrointestinal colonization with the microorganism Candida albicans to induce allergic sensitization to a coadministered protein antigen. They observed that colonization with C albicans was associated with a decrease in epithelial barrier function (tested by appearance of a fed antigen in the serum) and hypothesized that this barrier defect was playing a significant role in sensitization, although they did not address the likely contribution of PAMPs associated with C albicans. Taken together, facilitating antigen entry may promote allergic sensitization, although it is unlikely to do so in the absence of another TH2-promoting signal. Naive CD4 T cells are a pluripotent population capable of differentiating into a number of distinct phenotypes after activation by an APC. DCs are the most efficient cells for inducing naive T-cell activation and differentiation. Some differentiating T cells will become central memory T lymphocyte cells that will be maintained for long periods and home predominantly to lymph nodes, where they will be poised to expand and differentiate on future exposure to the same antigen. Effector TH memory cells, in contrast, secrete cytokines on activation and play a role in orchestrating the immune response to a particular antigen. Distinct effector populations can be defined by generally exclusive patterns of cytokine expression. TH2 cells have been defined by expression of IL-4, IL-5, and IL-13, whereas TH1 cells express high levels of IFN-γ, and TH17 cells express IL-17.25Murphy K.M. Reiner S.L. The lineage decisions of helper T cells.Nat Rev Immunol. 2002; 2: 933-944Crossref PubMed Scopus (963) Google Scholar, 26Harrington L.E. Mangan P.R. Weaver C.T. Expanding the effector CD4 T-cell repertoire: the Th17 lineage.Curr Opin Immunol. 2006; 18: 349-356Crossref PubMed Scopus (362) Google Scholar The dominant signal for differentiation toward the TH1 phenotype is IL-12 derived from DCs. IL-12 is sufficient for in vitro polarization of naive T cells to TH1, and in vivo knockout of either the p40 or p35 subunits of IL-12 results in a deficiency of TH1 cells.27Mattner F. Magram J. Ferrante J. Launois P. Di Padova K. Behin R. et al.Genetically resistant mice lacking interleukin-12 are susceptible to infection with Leishmania major and mount a polarized Th2 cell response.Eur J Immunol. 1996; 26: 1553-1559Crossref PubMed Scopus (356) Google Scholar DC-derived cytokines including IL-23 (which shares the p40 subunit with IL-12), IL-1, IL-6, and TGF-β (in the mouse) promote TH17 differentiation.28Laurence A. O'Shea J.J. TH-17 differentiation: of mice and men.Nat Immunol. 2007; 9: 903-905Crossref Scopus (88) Google Scholar In contrast, a necessary and sufficient, soluble, DC-derived signal for TH2 differentiation is not known. Naive T cells express the IL-4 receptor, and exogenous IL-4 promotes the development of TH2 cells in vitro. Furthermore, activated naive T cells can secrete low levels of IL-4, and this may contribute to TH2 differentiation in an autocrine and paracrine manner, especially in the absence of strong TH1-inducing signals.29Noben-Trauth N. Hu-Li J. Paul W.E. Conventional, naive CD4+ T cells provide an initial source of IL-4 during Th2 differentiation.J Immunol. 2000; 165: 3620-3625PubMed Google Scholar IL-4 is also a potent inhibitor of TH1 differentiation (as is IFN-γ an inhibitor of TH2), and this combination of cross-inhibition with positive feedback may help naive T cells commit to a TH2 differentiation pathway.25Murphy K.M. Reiner S.L. The lineage decisions of helper T cells.Nat Rev Immunol. 2002; 2: 933-944Crossref PubMed Scopus (963) Google Scholar In addition, innate cells such as mast cells and basophils have been shown to be potent sources of early IL-4, which can support TH2 differentiation.30Luccioli S. Brody D.T. Hasan S. Keane-Myers A. Prussin C. Metcalfe D.D. IgE(+), Kit(-), I-A/I-E(-) myeloid cells are the initial source of Il-4 after antigen challenge in a mouse model of allergic pulmonary inflammation.J Allergy Clin Immunol. 2002; 110: 117-124Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 31Oh K. Shen T. Le Gros G. Min B. Induction of Th2 type immunity in a mouse system reveals a novel immunoregulatory role of basophils.Blood. 2007; 109: 2921-2927PubMed Google Scholar However, DCs, which are thought to be the essential antigen-presenting population for the instruction of naive T cells, do not express IL-4 (or IL-13). Furthermore, both IL-4Rα and signal transducer and activator of transcription 6 knockout mice, which are incapable of responding to IL-4, still produce ample numbers of TH2 cells in response to experimental parasite infection.32Noben-Trauth N. Shultz L.D. Brombacher F. Urban Jr., J.F. Gu H. Paul W.E. An interleukin 4 (IL-4)-independent pathway for CD4+ T cell IL-4 production is revealed in IL-4 receptor-deficient mice.Proc Natl Acad Sci U S A. 1997; 94: 10838-10843Crossref PubMed Scopus (225) Google Scholar, 33Jankovic D. Kullberg M.C. Noben-Trauth N. Caspar P. Paul W.E. Sher A. Single cell analysis reveals that IL-4 receptor/Stat6 signaling is not required for the in vivo or in vitro development of CD4+ lymphocytes with a Th2 cytokine profile.J Immunol. 2000; 164: 3047-3055PubMed Google Scholar To whatever extent IL-4 and IL-13 from any source normally participate in early priming or amplification of TH2 differentiation, the cumulative data from knockouts of IL-4Rα, signal transducer and activator of transcription 6, and hematopoietic innate lineage–specific IL-4/IL-13 suggest that there are additional, IL-4/IL-13–independent pathways of TH2 differentiation.32Noben-Trauth N. Shultz L.D. Brombacher F. Urban Jr., J.F. Gu H. Paul W.E. An interleukin 4 (IL-4)-independent pathway for CD4+ T cell IL-4 production is revealed in IL-4 receptor-deficient mice.Proc Natl Acad Sci U S A. 1997; 94: 10838-10843Crossref PubMed Scopus (225) Google Scholar, 33Jankovic D. Kullberg M.C. Noben-Trauth N. Caspar P. Paul W.E. Sher A. Single cell analysis reveals that IL-4 receptor/Stat6 signaling is not required for the in vivo or in vitro development of CD4+ lymphocytes with a Th2 cytokine profile.J Immunol. 2000; 164: 3047-3055PubMed Google Scholar, 34Voehringer D. Reese T.A. Huang X. Shinkai K. Locksley R.M. Type 2 immunity is controlled by IL-4/IL-13 expression in hematopoietic non-eosinophil cells of the innate immune system.J Exp Med. 2006; 203: 1435-1446Crossref PubMed Scopus (141) Google Scholar This uncertainty regarding early TH2-inducing signals has contributed to the advancement of the default TH2 hypothesis, which posits that in the absence of TH1 or other polarizing signals, naive T cells preferentially differentiate into TH2 cells. Eisenbarth et al35Eisenbarth S.C. Piggott D.A. Huleatt J.W. Visintin I. Herrick C.A. Bottomly K. Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen.J Exp Med. 2002; 196: 1645-1651Crossref PubMed Scopus (712) Google Scholar were able to show that activation of DCs with low-dose exposure of LPS—sufficient for DCs to upregulate MHC class II and costimulatory molecules, but not for production of IL-12—induced TH2 immune responses in an in vivo allergic airway model. This supports the default hypothesis, because weakly activated DCs drove TH2 immunity in the absence of the TH1-polarizing signal from IL-12. In contrast with these data, Spörri et al36Spörri R. Reis e Sousa C. Inflammatory mediators are insufficient for full dendritic cell activation and promote expansion of CD4+ T cell populations lacking helper function.Nat Immunol. 2005; 6: 163-170Crossref PubMed Scopus (299) Google Scholar showed that DCs activated without direct ligation of TLR induced naive T-cell proliferation without commitment to TH1 or TH2. They used TLR-4 or MyD88 deficient/wild-type chimeric animals together with transgenic T cells to restrict the T-cell response to either the wild-type or TLR-signaling deficient DCs—both of which were activated by autocrine/paracrine effect of IL-15—to show that there was no default differentiation of T cells in response to intravenously administered antigen. To induce allergic sensitization rather than tolerance, adjuvants could have 1 of 2 effects: the selective migration and activation of an allergenic subset of DCs from the LP or within the Peyer patch, or the qualitative modulation of DC phenotype from tolerogenic to TH2-polarizing. In the lung, there are functionally distinct subsets of DCs, with myeloid DCs capable of promoting allergic sensitization and plasmacytoid DCs promoting inhalational tolerance.37de Heer H.J. Hammad H. Soullie T. Hijdra D. Vos N. Willart M.A. et al.Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen.J Exp Med. 2004; 200: 89-98Crossref PubMed Scopus (463) Google Scholar, 38Lambrecht B.N. De Veerman M. Coyle A.J. Gutierrez-Ramos J.C. Thielemans K. Pauwels R.A. Myeloid dendritic cells induce Th2 responses to inhaled antigen, leading to eosinophilic airway inflammation.J Clin Invest. 2000; 106: 551-559Crossref PubMed Google Scholar Within the gastrointestinal tract, it has also been shown that DC subsets differ in their cytokine secretion patterns and their ability to prime naive T cells to TH1, TH2, or regulatory T cells.39Bilsborough J. George T.C. Norment A. Viney J.L. Mucosal CD8alpha+ DC, with a plasmacytoid phenotype, induce differentiation and support function of T cells with regulatory properties.Immunology. 2003; 108: 481-492Crossref PubMed Scopus (161) Google Schola
Referência(s)