Abstract
Food allergy is the major reason for severe anaphylaxis in childhood and adolescence. Currently, effective and safe treatments for food allergy are unavailable. Allergen-specific CD4+ T cells have a pivotal role in causing and maintaining the allergic response to food allergens. The purpose of this review is to provide an overview on the role of allergen-specific T cells in food allergy during allergic sensitization, natural tolerance development and allergen immunotherapy. Allergen-specific T cells in the context of food allergy are predominantly of a Th2 type with slightly different surface marker expression patterns in different food allergies. During the process of reverting food allergy to a status of tolerance or sustained unresponsiveness there is a loss of this Th2 committed compartment with an asymptotic approximation to a regulatory and Th0/Th1 dominated compartment seen in non-allergic individuals. This process is accompanied by a significant reduction of absolute frequencies of allergen-specific T cells. Particularly, regulatory T cells may provide significant help to achieve sustained control of the effector cell populations via suppression of effector cell function and possibly induction of blocking antibodies.
Similar content being viewed by others
References
Akdis CA, Akdis M (2015) Mechanisms of allergen-specific immunotherapy and immune tolerance to allergens. World Allergy Organ J 8:17
Akdis M, Aab A, Altunbulakli C et al (2016) Interleukins (from IL-1 to IL-38), interferons, transforming growth factor beta, and TNF-alpha: Receptors, functions, and roles in diseases. J Allergy Clin Immunol 138:984–1010
Archila LD, Jeong D, Pascal M et al (2015) Jug r 2-reactive CD4(+) T cells have a dominant immune role in walnut allergy. J Allergy Clin Immunol 136:983–992.e7
Archila LD, Chow IT, McGinty JW et al (2016) Ana o 1 and Ana o 2 cashew allergens share cross-reactive CD4(+) T cell epitopes with other tree nuts. Clin Exp Allergy 46:871–883
Arrieta MC, Stiemsma LT, Dimitriu PA et al (2015) Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci Transl Med 7:307ra152
Ashley SE, Tan HT, Vuillermin P et al (2017) The skin barrier function gene SPINK5 is associated with challenge-proven IgE-mediated food allergy in infants. Allergy 72:1356–1364
Bahnson HT, du Toit G, Lack G (2017) Statistical considerations of food allergy prevention studies. J Allergy Clin Immunol Pract 5:274–282
Bedoret D, Singh AK, Shaw V et al (2012) Changes in antigen-specific T-cell number and function during oral desensitization in cow’s milk allergy enabled with omalizumab. Mucosal Immunol 5:267–276
Belkaid Y, Segre JA (2014) Dialogue between skin microbiota and immunity. Science 346:954–959
Bellach J, Schwarz V, Ahrens B et al (2017) Randomized placebo-controlled trial of hen’s egg consumption for primary prevention in infants. J Allergy Clin Immunol 139:1591–1599.e2
Blom LH, Martel BC, Larsen LF et al (2017) The immunoglobulin superfamily member CD200R identifies cells involved in type 2 immune responses. Allergy 72:1081–1090
Bonnet B, Vigneron J, Levacher B et al (2016) Low-dose IL-2 induces regulatory T cell-mediated control of experimental food allergy. J Immunol 197:188–198
Breiteneder H, Radauer C (2004) A classification of plant food allergens. J Allergy Clin Immunol 113:821–830 quiz 831
Brough HA, Cousins DJ, Munteanu A et al (2014) IL-9 is a key component of memory TH cell peanut-specific responses from children with peanut allergy. J Allergy Clin Immunol 134:1329–1338.e1310
Bublin M, Eiwegger T, Breiteneder H (2014) Do lipids influence the allergic sensitization process? J Allergy Clin Immunol 134:521–529
Burks AW, Jones SM, Wood RA et al (2012) Oral immunotherapy for treatment of egg allergy in children. N Engl J Med 367:233–243
Caubet JC, Bencharitiwong R, Moshier E et al (2012) Significance of ovomucoid- and ovalbumin-specific IgE/IgG(4) ratios in egg allergy. J Allergy Clin Immunol 129:739–747
Caubet JC, Lin J, Ahrens B et al (2017) Natural tolerance development in cow’s milk allergic children:IgE and IgG4 epitope binding. Allergy 72:1677–1685
Chattopadhyay PK, Yu J, Roederer M (2005) A live-cell assay to detect antigen-specific CD4+ T cells with diverse cytokine profiles. Nat Med 11:1113–1117
Chen CY, Lee JB, Liu B et al (2015) Induction of interleukin-9-producing mucosal mast cells promotes susceptibility to IgE-mediated experimental food allergy. Immunity 43:788–802
Chinthrajah RS, Tupa D, Prince BT et al (2015) Diagnosis of food allergy. Pediatr Clin N Am 62:1393–1408
Chinthrajah RS, Hernandez JD, Boyd SD et al (2016) Molecular and cellular mechanisms of food allergy and food tolerance. J Allergy Clin Immunol 137:984–997
Chu DK, Llop-Guevara A, Walker TD et al (2013) IL-33, but not thymic stromal lymphopoietin or IL-25, is central to mite and peanut allergic sensitization. J Allergy Clin Immunol 131:187–200.e1–8
de Silva D, Geromi M, Halken S et al (2014) Primary prevention of food allergy in children and adults: systematic review. Allergy 69:581–589
DeLong JH, Simpson KH, Wambre E et al (2011) Ara h 1-reactive T cells in individuals with peanut allergy. J Allergy Clin Immunol 127:1211–1218.e3
Diesner SC, Bergmayr C, Pfitzner B et al (2016) A distinct microbiota composition is associated with protection from food allergy in an oral mouse immunization model. Clin Immunol 173:10–18
Du Toit G, Roberts G, Sayre PH et al (2015) Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med 372:803–813
Du Toit G, Sayre PH, Roberts G et al (2016) Effect of Avoidance on peanut allergy after early peanut consumption. N Engl J Med 374:1435–1443
Eiwegger T, Akdis CA (2011) IL-33 links tissue cells, dendritic cells and Th2 cell development in a mouse model of asthma. Eur J Immunol 41:1535–1538
Eiwegger T, Rigby N, Mondoulet L et al (2006) Gastro-duodenal digestion products of the major peanut allergen Ara h 1 retain an allergenic potential. Clin Exp Allergy 36:1281–1288
Fishbein AB, Qamar N, Erickson KA et al (2014) Cytokine responses to egg protein in previously allergic children who developed tolerance naturally. Ann Allergy Asthma Immunol 113:667–670.e4
Flinterman AE, Pasmans SG, den Hartog Jager CF et al (2010) T cell responses to major peanut allergens in children with and without peanut allergy. Clin Exp Allergy 40:590–597
Frischmeyer-Guerrerio PA, Masilamani M, Gu W et al (2017) Mechanistic correlates of clinical responses to omalizumab in the setting of oral immunotherapy for milk allergy. J Allergy Clin Immunol 140:1043–1053.e8
Frossard CP, Zimmerli SC, Rincon Garriz JM et al (2015) Food allergy in mice is modulated through the thymic stromal lymphopoietin pathway. Clin Transl Allergy 6:2
Fuentes-Aparicio V, Alonso-Lebrero E, Zapatero L et al (2012) Oral immunotherapy in hen’s egg-allergic children increases a hypo-proliferative subset of CD4+ T cells that could constitute a marker of tolerance achievement. Pediatr Allergy Immunol 23:648–653
Fujimura KE, Sitarik AR, Havstad S et al (2016) Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation. Nat Med 22:1187–1191
Gorelik M, Narisety SD, Guerrerio AL et al (2015) Suppression of the immunologic response to peanut during immunotherapy is often transient. J Allergy Clin Immunol 135:1283–1292
Grabenhenrich LB, Dölle S, Moneret-Vautrin A et al (2016) Anaphylaxis in children and adolescents: The European Anaphylaxis Registry. J Allergy Clin Immunol 137:1128–1137 :.e1
Greenhawt MJ, Fleischer DM (2017) Primary prevention of food allergy. Curr Allergy Asthma Rep 17:26
Hochstadter E, Clarke A, De Schryver S et al (2016) Increasing visits for anaphylaxis and the benefits of early epinephrine administration: a 4-year study at a pediatric emergency department in Montreal, Canada. J Allergy Clin Immunol 137:1888–1890.e4
Hussain M, Borcard L, Walsh KP et al (2017) Basophil-derived interleukin-4 promotes epicutaneous antigen sensitization concomitant with the development of food allergy. J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2017.02.035
Irvine AD, McLean WH, Leung DY (2011) Filaggrin mutations associated with skin and allergic diseases. N Engl J Med 365:1315–1327
Jiang H, Hener P, Li J et al (2012) Skin thymic stromal lymphopoietin promotes airway sensitization to inhalant house dust mites leading to allergic asthma in mice. Allergy 67:1078–1082
Jones SM, Pons L, Roberts JL et al (2009) Clinical efficacy and immune regulation with peanut oral immunotherapy. J Allergy Clin Immunol 124:292–300 300.e1–97
Jones SM, Sicherer SH, Burks AW et al (2017) Epicutaneous immunotherapy for the treatment of peanut allergy in children and young adults. J Allergy Clin Immunol 139:1242–1252 :.e9
Jutel M, Akdis CA (2011) T-cell subset regulation in atopy. Curr Allergy Asthma Rep 11:139–145
Karlsson MR, Rugtveit J, Brandtzaeg P (2004) Allergen-responsive CD4+ CD25+ regulatory T cells in children who have outgrown cow’s milk allergy. J Exp Med 199:1679–1688
Kattan J (2016) The prevalence and natural history of food allergy. Curr Allergy Asthma Rep 16:47
Kelleher MM, Dunn-Galvin A, Gray C et al (2016) Skin barrier impairment at birth predicts food allergy at 2 years of age. J Allergy Clin Immunol 137:1111–1116.e8
Kim EH, Bird JA, Kulis M et al (2011a) Sublingual immunotherapy for peanut allergy: clinical and immunologic evidence of desensitization. J Allergy Clin Immunol 127:640–646 :.e1
Kim JS, Nowak-Wegrzyn A, Sicherer SH et al (2011b) Dietary baked milk accelerates the resolution of cow’s milk allergy in children. J Allergy Clin Immunol 128:125–131.e2
Knaysi G, Smith AR, Wilson JM et al (2017) The skin as a route of allergen exposure: Part II. Allergens and role of the microbiome and environmental exposures. Curr Allergy Asthma Rep 17:7
Lack G, Fox D, Northstone K et al (2003) Factors associated with the development of peanut allergy in childhood. N Engl J Med 348:977–985
Lanser BJ, Wright BL, Orgel KA et al (2015) Current options for the treatment of food allergy. Pediatr Clin N Am 62:1531–1549
Li J, Wang Y, Tang L et al (2013) Dietary medium-chain triglycerides promote oral allergic sensitization and orally induced anaphylaxis to peanut protein in mice. J Allergy Clin Immunol 131:442–450
Licona-Limon P, Kim LK, Palm NW et al (2013) TH2, allergy and group 2 innate lymphoid cells. Nat Immunol 14:536–542
Luyt D, Ball H, Makwana N et al (2014) BSACI guideline for the diagnosis and management of cow’s milk allergy. Clin Exp Allergy 44:642–672
Mahesh PA, Wong GW, Ogorodova L et al (2016) Prevalence of food sensitization and probable food allergy among adults in India: the EuroPrevall INCO study. Allergy 71:1010–1019
Mayer E, Bannert C, Gruber S et al (2012) Cord blood derived CD4+ CD25(high) T cells become functional regulatory T cells upon antigen encounter. PLoS One 7:e29355
Michaud B, Aroulandom J, Baiz N et al (2014) Casein-specific IL-4- and IL-13-secreting T cells: a tool to implement diagnosis of cow’s milk allergy. Allergy 69:1473–1480
Mitson-Salazar A, Yin Y, Wansley DL et al (2016) Hematopoietic prostaglandin D synthase defines a proeosinophilic pathogenic effector human T(H)2 cell subpopulation with enhanced function. J Allergy Clin Immunol 137:907–918.e9
Mobs C, Ipsen H, Mayer L et al (2012) Birch pollen immunotherapy results in long-term loss of Bet v 1-specific TH2 responses, transient TR1 activation, and synthesis of IgE-blocking antibodies. J Allergy Clin Immunol 130:1108–1116.e6
Moghaddam AE, Hillson WR, Noti M et al (2014) Dry roasting enhances peanut-induced allergic sensitization across mucosal and cutaneous routes in mice. J Allergy Clin Immunol 134:1453–1456
Muraro A, Halken S, Arshad SH et al (2014) EAACI food allergy and anaphylaxis guidelines. Primary prevention of food allergy. Allergy 69:590–601
Noti M, Kim BS, Siracusa MC et al (2014) Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin-basophil axis. J Allergy Clin Immunol 133:1390–1399 1399.e1–6
Noval Rivas M, Burton OT, Oettgen HC et al (2016) IL-4 production by group 2 innate lymphoid cells promotes food allergy by blocking regulatory T-cell function. J Allergy Clin Immunol 138:801–811.e9
Nurmatov U, Dhami S, Arasi S et al (2017) Allergen immunotherapy for IgE-mediated food allergy: a systematic review and meta-analysis. Allergy 72:1133–1147
Nwaru BI, Hickstein L, Panesar SS et al (2014) Prevalence of common food allergies in Europe: a systematic review. and meta-analysis. Allergy 69:992–1007
Obersteiner A, Gilles S, Frank U et al (2016) Pollen-associated microbiome correlates with pollution parameters and the allergenicity of pollen. PLoS One 11:e0149545
Paparo L, Nocerino R, Cosenza L et al (2016) Epigenetic features of FoxP3 in children with cow’s milk allergy. Clin Epigenetics 8:86
Pascal M, Konstantinou GN, Masilamani M et al (2013) In silico prediction of Ara h 2 T cell epitopes in peanut-allergic children. Clin Exp Allergy 43:116–127
Perkin MR, Logan K, Marrs T et al (2016) randomized trial of introduction of allergenic foods in breast-fed infants. N Engl J Med 374:1733–1743
Platzer B, Stout M, Fiebiger E (2015) Functions of dendritic-cell-bound IgE in allergy. Mol Immunol 68(2 Pt A):116–119
Ponce M, Diesner SC, Szepfalusi Z et al (2016) Markers of tolerance development to food allergens. Allergy 71:1393–1404
Poulsen LK, Ladics GS, McClain S et al (2014) Sensitizing properties of proteins: executive summary. Clin Transl Allergy 4:10
Prussin C, Lee J, Foster B (2009) Eosinophilic gastrointestinal disease and peanut allergy are alternatively associated with IL-5+ and IL-5(−) T(H)2 responses. J Allergy Clin Immunol 124:1326–1332.e6
Qamar N, Fishbein AB, Erickson KA et al (2015) Naturally occurring tolerance acquisition to foods in previously allergic children is characterized by antigen specificity and associated with increased subsets of regulatory T cells. Clin Exp Allergy 45:1663–1672
Ramesh M, Yuenyongviwat A, Konstantinou GN et al (2016) Peanut T-cell epitope discovery: Ara h 1. J Allergy Clin Immunol 137:1764–1771.e4
Renand A, Newbrough S, Wambre E et al (2014) Arginine kinase Pen m 2 as an important shrimp allergen recognized by TH2 cells. J Allergy Clin Immunol 134:1456–1459 :.e7
Ruiter B, Shreffler WG (2012) The role of dendritic cells in food allergy. J Allergy Clin Immunol 129:921–928
Ryan JF, Hovde R, Glanville J et al (2016) Successful immunotherapy induces previously unidentified allergen-specific CD4+ T-cell subsets. Proc Natl Acad Sci USA 113:E1286–E1295
Sampson HA, Aceves S, Bock SA et al (2014) Food allergy: a practice parameter update-2014. J Allergy Clin Immunol 134:1016–1025.e43
Santos AF, James LK, Bahnson HT et al (2015) IgG4 inhibits peanut-induced basophil and mast cell activation in peanut-tolerant children sensitized to peanut major allergens. J Allergy Clin Immunol 135:1249–1256
Savage J, Sicherer S, Wood R (2016) The natural history of food allergy. J Allergy Clin Immunol Pract 4:196–203 quiz 204
Savilahti EM, Karinen S, Salo HM et al (2010) Combined T regulatory cell and Th2 expression profile identifies children with cow’s milk allergy. Clin Immunol 136:16–20
Shreffler WG, Wanich N, Moloney M et al (2009) Association of allergen-specific regulatory T cells with the onset of clinical tolerance to milk protein. J Allergy Clin Immunol 123:43–52.e7
Sicherer SH, Wood RA, Vickery BP et al (2014) The natural history of egg allergy in an observational cohort. J Allergy Clin Immunol 133:492–499
Simons FE, Ebisawa M, Sanchez-Borges M et al (2015) 2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines. World Allergy Organ J 8:32
Simpson EL, Irvine AD et al (2016) Update on epidemiology, diagnosis, and disease course of atopic dermatitis. Semin Cutan Med Surg 35(5 Suppl):S84–S88
Smith PK, Masilamani M, Li XM et al (2017) The false alarm hypothesis: Food allergy is associated with high dietary advanced glycation end-products and proglycating dietary sugars that mimic alarmins. J Allergy Clin Immunol 139:429–437
Sommanus S, Kerddonfak S, Kamchaisatian W et al (2014) Cow’s milk protein allergy: immunological response in children with cow’s milk protein tolerance Asian Pac. J Allergy Immunol 32:171–177
Soyka MB, Holzmann D, Basinski TM et al (2015) The Induction of IL-33 in the sinus epithelium and its influence on T-helper cell responses. PLoS One 10:e0123163
Stojadinovic M, Pieters R, Smit J et al (2014) Cross-linking of beta-lactoglobulin enhances allergic sensitization through changes in cellular uptake and processing. Toxicol Sci 140:224–235
Subbarayal B, Schiller D, Möbs C et al (2015) The diversity of Bet v 1-specific IgG4 antibodies remains mostly constant during the course of birch pollen immunotherapy. J Allergy Clin Immunol 136:1680–1682.e3
Syed A, Garcia MA, Lyu SC et al (2014) Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3). J Allergy Clin Immunol 133:500–510
Tiemessen MM, Van Ieperen-Van Dijk AG, Bruijnzeel-Koomen CA et al (2004) Cow’s milk-specific T-cell reactivity of children with and without persistent cow’s milk allergy: key role for IL-10. J Allergy Clin Immunol 113:932–939
Togias A, Cooper SF, Acebal ML et al (2017) Addendum guidelines for the prevention of peanut allergy in the United States: summary of the National Institute of Allergy and Infectious Diseases-sponsored expert panel. Pediatr Dermatol 34:5–12
Tordesillas L, Goswami R, Benedé S et al (2014) Skin exposure promotes a Th2-dependent sensitization to peanut allergens. J Clin Invest 124:4965–4975
Turcanu V, Maleki SJ, Lack G (2003) Characterization of lymphocyte responses to peanuts in normal children, peanut-allergic children, and allergic children who acquired tolerance to peanuts. J Clin Invest 111:1065–1072
Turcanu V, Winterbotham M, Kelleher P et al (2008) Peanut-specific B and T cell responses are correlated in peanut-allergic but not in non-allergic individuals. Clin Exp Allergy 38:1132–1139
van de Veen W, Stanic B, Yaman G et al (2013) IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses. J Allergy Clin Immunol 131:1204–1212
Varshney P et al (2011) A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response. J Allergy Clin Immunol 127:654–660
Vickery BP, Scurlock AM, Kulis M et al (2014) Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy. J Allergy Clin Immunol 133:468–475
Wambre E, Van Overtvelt L, Maillère B et al (2008) Single cell assessment of allergen-specific T cell responses with MHC class II peptide tetramers: methodological aspects. Int Arch Allergy Immunol 146:99–112
Wambre E, DeLong JH, James EA et al (2014) Specific immunotherapy modifies allergen-specific CD4(+) T-cell responses in an epitope-dependent manner. J Allergy Clin Immunol 133:872–879.e7
Wambre E, Bajzik V, DeLong JH et al (2017) A phenotypically and functionally distinct human TH2 cell subpopulation is associated with allergic disorders. Sci Transl Med 9 pii:eaam9171
Wang YH (2016) Developing food allergy: a potential immunologic pathway linking skin barrier to gut. F1000Res 5 pii: F1000
Werfel T, Asero R, Ballmer-Weber BK et al (2015) Position paper of the EAACI: food allergy due to immunological cross-reactions with common inhalant allergens. Allergy 70:1079–1090
Westerholm-Ormio M, Vaarala O, Tiittanen M et al (2010) Infiltration of Foxp3- and Toll-like receptor-4-positive cells in the intestines of children with food allergy. J Pediatr Gastroenterol Nutr 50:367–376
Wisniewski JA, Commins SP, Agrawal R et al (2015) Analysis of cytokine production by peanut-reactive T cells identifies residual Th2 effectors in highly allergic children who received peanut oral immunotherapy. Clin Exp Allergy 45:1201–1213
Wood RA, Sicherer SH, Vickery BP et al (2013) The natural history of milk allergy in an observational cohort. J Allergy Clin Immunol 131:805–812
Wood RA, Kim JS, Lindblad R et al (2016) A randomized, double-blind, placebo-controlled study of omalizumab combined with oral immunotherapy for the treatment of cow’s milk allergy. J Allergy Clin Immunol 137:1103–1110.e11
Worm M, Moneret-Vautrin A, Scherer K et al (2014) First European data from the network of severe allergic reactions (NORA). Allergy 69:1397–1404
Wright BL, Kulis M, Orgel KA et al (2016) Component-resolved analysis of IgA, IgE, and IgG4 during egg OIT identifies markers associated with sustained unresponsiveness. Allergy 71:1552–1560
Xie J, Lotoski LC, Chooniedass R et al (2012) Elevated antigen-driven IL-9 responses are prominent in peanut allergic humans. PLoS One 7:e45377
Zhang H, Kong H, Zeng X et al (2014) Subsets of regulatory T cells and their roles in allergy. J Transl Med 12:125
Acknowledgements
This work was supported by Grants from: Islamic Development Bank Merit Scholarship Programme for 1433H (2012-13), HSBC Bank Canada Catalyst Research Grant from The Hospital for Sick Children, Innovation Fund Denmark #6159-00005A.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
About this article
Cite this article
Saidova, A., Hershkop, A.M., Ponce, M. et al. Allergen-Specific T Cells in IgE-Mediated Food Allergy. Arch. Immunol. Ther. Exp. 66, 161–170 (2018). https://doi.org/10.1007/s00005-017-0501-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00005-017-0501-7