Common and Distinct Roles for TH2 and TFH Cells in Shaping the Spectrum of Allergic Diseases.

Sensitization to environmental and food antigens leading to hyperresponsive type 2 immune responses have increased to alarming proportions and results in various diseases, including asthma, food allergy (FA), and atopic dermatitis (AD). The pathophysiologic mechanisms of type 2 allergic diseases involve both antibody-mediated (IgE isotype) and type 2 TH cell–mediated mechanisms that drive inflammation.1Gowthaman U. Sikder S. Lee D. Fisher C. T follicular helper cells in IgE-mediated pathologies.Curr Opin Immunol. 2022; 74: 133-139Crossref Scopus (1) Google Scholar The IgE isotype has always been linked to atopy, allergy, and asthma, as it provides a mechanistic link for allergen recognition and the effector functions of mast cells and basophils following allergen exposure.1Gowthaman U. Sikder S. Lee D. Fisher C. T follicular helper cells in IgE-mediated pathologies.Curr Opin Immunol. 2022; 74: 133-139Crossref Scopus (1) Google Scholar Historically, TH2 effector cells were considered to be the sole T-cell subset that could mediate all manifestations of allergic disease, including helping B cells make IgE antibodies as well as cell-mediated tissue inflammation. However, this notion has been changing lately, as a distinct subset of CD4 T cells called T follicular helper (TFH) cells were identified as dedicated helpers of B cells, helping them to drive antibody production, including IgE, in many type 2 disease models.1Gowthaman U. Sikder S. Lee D. Fisher C. T follicular helper cells in IgE-mediated pathologies.Curr Opin Immunol. 2022; 74: 133-139Crossref Scopus (1) Google Scholar,2Keet C.A. Berin M.C. The year in food allergy.J Allergy Clin Immunol. 2022; 149: 867-873Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Although both TFH and TH2 effector cells can express the IgE switch factor IL-4, TFH cells are distinct from TH2 effector cells owing to their unique ability to home to B-cell areas and promote class-switching and antibody affinity maturation. Thus, a functional dichotomy between TH2 effector cells directly modulating inflammation in tissues and TFH cells in secondary lymphoid organs regulating peripheral inflammation via IgE modulation has begun to emerge. With this distinction, a fresh look at type 2 diseases reveals both distinct and collective roles for TH2 effector cells and TFH cells in dictating type 2 disease states (Fig 1).Allergic diseases, TH2 effector cells, and TFH cellsAllergic diseases often manifest at barrier sites such as the lung, gut, and skin. Asthma remains one of the most prevalent allergic diseases. Asthma can be broadly categorized as type 2high (or T2) and type 2low asthma. T2 asthma is the most prevalent type of asthma and is driven by aberrant type 2 responses such as the accumulation of TH2 effector cells, eosinophils, and group 2 innate lymphoid cells (ILC2s) in the lung.3Hammad H. Lambrecht B.N. The basic immunology of asthma.Cell. 2021; 184: 1469-1485Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar,4Ray A. Camiolo M. Fitzpatrick A. Gauthier M. Wenzel S.E. Are we meeting the promise of endotypes and precision medicine in asthma?.Physiol Rev. 2020; 100: 983-1017Crossref PubMed Scopus (37) Google Scholar In contrast, type 2low asthma is mediated by the infiltration of neutrophils in the lung. Both IgE-associated and IgE-independent T2 asthma endotypes exist in humans.4Ray A. Camiolo M. Fitzpatrick A. Gauthier M. Wenzel S.E. Are we meeting the promise of endotypes and precision medicine in asthma?.Physiol Rev. 2020; 100: 983-1017Crossref PubMed Scopus (37) Google Scholar However, mouse studies have shown that many of the asthma clinical features could be replicated independently of IgE or TFH cells, and thus the disease seems to be predominantly TH2 effector cell–mediated.1Gowthaman U. Sikder S. Lee D. Fisher C. T follicular helper cells in IgE-mediated pathologies.Curr Opin Immunol. 2022; 74: 133-139Crossref Scopus (1) Google Scholar,4Ray A. Camiolo M. Fitzpatrick A. Gauthier M. Wenzel S.E. Are we meeting the promise of endotypes and precision medicine in asthma?.Physiol Rev. 2020; 100: 983-1017Crossref PubMed Scopus (37) Google Scholar Although TFH cells have been shown to convert to TH2 effector cells, the conversion may not be an absolute necessity, as mouse models of asthma with T-cell–specific deletion of Bcl6, which abrogates TFH cell development, have intact TH2 cell induction and lung inflammation, including eosinophilia.1Gowthaman U. Sikder S. Lee D. Fisher C. T follicular helper cells in IgE-mediated pathologies.Curr Opin Immunol. 2022; 74: 133-139Crossref Scopus (1) Google Scholar,5He K. Hettinga A. Kale S.L. Hu S. Xie M.M. Dent A.L. et al.Blimp-1 is essential for allergen-induced asthma and Th2 cell development in the lung.J Exp Med. 2020; : 217Google Scholar Conversely, in mouse models of T-cell–specific Blimp1 deletion, the development TH2 effector cells, but not TFH cells and IgE, is abrogated, which results in protection against eosinophilia and airway hyperresponsiveness to airway allergens.5He K. Hettinga A. Kale S.L. Hu S. Xie M.M. Dent A.L. et al.Blimp-1 is essential for allergen-induced asthma and Th2 cell development in the lung.J Exp Med. 2020; : 217Google Scholar Nevertheless, IgE antibodies may act as amplifiers of the disease, as anti-IgE therapy has some beneficial effects in some patients, and adoptive transfer of IgE in mice and subsequent challenge result in asthma-like symptoms.1Gowthaman U. Sikder S. Lee D. Fisher C. T follicular helper cells in IgE-mediated pathologies.Curr Opin Immunol. 2022; 74: 133-139Crossref Scopus (1) Google Scholar,3Hammad H. Lambrecht B.N. The basic immunology of asthma.Cell. 2021; 184: 1469-1485Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar,4Ray A. Camiolo M. Fitzpatrick A. Gauthier M. Wenzel S.E. Are we meeting the promise of endotypes and precision medicine in asthma?.Physiol Rev. 2020; 100: 983-1017Crossref PubMed Scopus (37) Google ScholarAllergic response to food is the immune-mediated adverse reaction that occurs reproducibly following exposure to a particular food. The allergic response to food ranges from immediate hypersensitivity reactions (including anaphylactic response) occurring within minutes to hours of exposure to a chronic inflammatory response such as that in eosinophilic esophagitis (EoE).2Keet C.A. Berin M.C. The year in food allergy.J Allergy Clin Immunol. 2022; 149: 867-873Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,6Hill D.A. Spergel J.M. The immunologic mechanisms of eosinophilic esophagitis.Curr Allergy Asthma Rep. 2016; 16: 1-15Crossref Scopus (40) Google Scholar The immediate anaphylactic response to food antigens is primarily IgE dependent and thus likely TFH cell–dependent. Indeed, genetic mouse models that specifically lack TFH cells show severely impaired IgE elicitation as well as anaphylaxis in response to food allergens.1Gowthaman U. Sikder S. Lee D. Fisher C. T follicular helper cells in IgE-mediated pathologies.Curr Opin Immunol. 2022; 74: 133-139Crossref Scopus (1) Google Scholar,2Keet C.A. Berin M.C. The year in food allergy.J Allergy Clin Immunol. 2022; 149: 867-873Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Although it could be hypothesized that IgE responses to food allergens are also TFH cell–dependent in humans, a distinctive population of circulating TH2 cells (TH2A cells) have been identified in patients with FA.7Berin M.C. Agashe C. Burks A.W. Chiang D. Davidson W.F. Dawson P. et al.Allergen-specific T cells and clinical features of food allergy: lessons from CoFAR immunotherapy cohorts.J Allergy Clin Immunol. 2022; 149: 1373-1382.e12Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Whether these cells are related to TFH cells and whether they affect food-specific IgE remains unclear. In contrast to what occurs in FA, in EoE, the primary disease mechanism seems to be non–IgE-mediated eosinophilic infiltration of the esophagus despite the disease presenting itself with comorbid allergic conditions, including asthma and IgE-mediated FA.6Hill D.A. Spergel J.M. The immunologic mechanisms of eosinophilic esophagitis.Curr Allergy Asthma Rep. 2016; 16: 1-15Crossref Scopus (40) Google Scholar Indeed, anti-IgE therapy (omalizumab) does not seem to have any benefit in EoE; however, it has shown some promising results in patients with FA, especially in conjunction with oral immunotherapy.2Keet C.A. Berin M.C. The year in food allergy.J Allergy Clin Immunol. 2022; 149: 867-873Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Thus, it is likely that the key drivers of eosinophilic infiltration in EoE are TH2 effector cells and ILC2s. Whether EoE can be induced in mouse models that specifically lack TFH cells remains underexplored.Yet another major type 2 inflammatory disease is AD, in which the skin is the major barrier site affected. AD is often triggered by barrier dysfunction followed by skin dysbiosis and environmental allergen exposure, and it is typified by pruritus and inflammatory skin lesions.8Czarnowicki T. He H. Krueger J.G. Guttman-Yassky E. Atopic dermatitis endotypes and implications for targeted therapeutics.J Allergy Clin Immunol. 2019; 143: 1-11Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar Although high IgE levels are often associated with AD, especially in the extrinsic type affecting the majority of people, IgE does not seem to be the main driver of the disease.8Czarnowicki T. He H. Krueger J.G. Guttman-Yassky E. Atopic dermatitis endotypes and implications for targeted therapeutics.J Allergy Clin Immunol. 2019; 143: 1-11Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar Indeed, AD can be induced in mouse models independently of IgE, and anti-IgE therapy in patients has not had a significant effect and is not indicated as a therapy for AD.8Czarnowicki T. He H. Krueger J.G. Guttman-Yassky E. Atopic dermatitis endotypes and implications for targeted therapeutics.J Allergy Clin Immunol. 2019; 143: 1-11Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar,9Haddad E.-B. Cyr S.L. Arima K. McDonald R.A. Levit N.A. Nestle F.O. Current and emerging strategies to inhibit type 2 inflammation in atopic dermatitis.Dermatol Ther (Heidelb). 2022; 12: 1501-1533Crossref PubMed Scopus (1) Google Scholar In contrast, TH2 cells and mast cells in the skin have been shown to produce a variety of cytokines, including IL-4, IL-13, and IL-31, which mediate major aspects of AD pathophysiology, including itch, inflammation, and skin barrier disruption.8Czarnowicki T. He H. Krueger J.G. Guttman-Yassky E. Atopic dermatitis endotypes and implications for targeted therapeutics.J Allergy Clin Immunol. 2019; 143: 1-11Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar Indeed, clinical studies have demonstrated that targeting these cytokines with dupilumab (IL-4 and IL-13) or nemolizumab (IL-31) for example, is effective in alleviating AD symptoms.9Haddad E.-B. Cyr S.L. Arima K. McDonald R.A. Levit N.A. Nestle F.O. Current and emerging strategies to inhibit type 2 inflammation in atopic dermatitis.Dermatol Ther (Heidelb). 2022; 12: 1501-1533Crossref PubMed Scopus (1) Google Scholar In contrast, whereas TFH cells can be induced in animal models of AD and are present in increased numbers in patients with AD, their contribution to the disease is unclear.1Gowthaman U. Sikder S. Lee D. Fisher C. T follicular helper cells in IgE-mediated pathologies.Curr Opin Immunol. 2022; 74: 133-139Crossref Scopus (1) Google Scholar Given that IgE may be only a minor player in AD pathogenesis, it is likely that TH2 effector cells rather than TFH cells may be the major drivers of this disease.Type 2 T-cell heterogeneity, disease endotypes, and the road to precision medicineType 2 diseases are complex and heterogenous, and the terminology used to describe these diseases, such as asthma, AD, and FA, consists of broad umbrella terms that represent a group of diseases.3Hammad H. Lambrecht B.N. The basic immunology of asthma.Cell. 2021; 184: 1469-1485Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar,8Czarnowicki T. He H. Krueger J.G. Guttman-Yassky E. Atopic dermatitis endotypes and implications for targeted therapeutics.J Allergy Clin Immunol. 2019; 143: 1-11Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar The term endotype is used to characterize each subtype of the disease on the basis of its specific pathophysiology and biomarker signatures. The most significant efforts toward endotyping based on demographics, clinical variables, and multi-omics biomarker analysis have been for asthma.3Hammad H. Lambrecht B.N. The basic immunology of asthma.Cell. 2021; 184: 1469-1485Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar,4Ray A. Camiolo M. Fitzpatrick A. Gauthier M. Wenzel S.E. Are we meeting the promise of endotypes and precision medicine in asthma?.Physiol Rev. 2020; 100: 983-1017Crossref PubMed Scopus (37) Google Scholar On the basis of these analyses, at least 3 categories of type 2 asthma (2 endotypes of allergic asthma and 1 endotype of nonallergic, late-onset eosinophilic asthma) seem to emerge. Although the pathophysiology of early-onset, eosinophilic, type 2 allergic asthma is likely driven by TH2 cells and by TFH cell–driven IgE, what drives the steroid-resistant, late-onset, nonallergic, eosinophilic asthma endotype is unclear; with ILC2s believed to be the likely players here.4Ray A. Camiolo M. Fitzpatrick A. Gauthier M. Wenzel S.E. Are we meeting the promise of endotypes and precision medicine in asthma?.Physiol Rev. 2020; 100: 983-1017Crossref PubMed Scopus (37) Google Scholar Complicating this further has been the identification of additional subsets that aid TH2 effector cell response in mouse models of asthma such as IL-21–producing CD4 T cells or TH9 cells in the lung.3Hammad H. Lambrecht B.N. The basic immunology of asthma.Cell. 2021; 184: 1469-1485Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar The extent to which these cell populations influence the severity of the human disease is currently unclear. Endotypic classifications for AD, which are largely based on clinical variables and biomarker analysis, have also been proposed.8Czarnowicki T. He H. Krueger J.G. Guttman-Yassky E. Atopic dermatitis endotypes and implications for targeted therapeutics.J Allergy Clin Immunol. 2019; 143: 1-11Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar In AD, a TH2 signature seems to be central to the disease, with endotypes defined as having other cytokine signatures such as TH17, TH1, and TH22 cells concomitant with the TH2 cytokine profile.8Czarnowicki T. He H. Krueger J.G. Guttman-Yassky E. Atopic dermatitis endotypes and implications for targeted therapeutics.J Allergy Clin Immunol. 2019; 143: 1-11Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar Compared with endotyping in AD or asthma, endotyping in FA is in its early days and is an emerging area of interest.As already described for various type 2 diseases, TH2 effector cells and TFH cells produce distinct mechanistic mediators that in turn drive disease phenotypes. That said, however, recent evidence from both clinical and animal models highlights the importance of heterogeneity within TH2 effector cells and TFH cell compartments in shaping various type 2 disease states or their endotypes.1Gowthaman U. Sikder S. Lee D. Fisher C. T follicular helper cells in IgE-mediated pathologies.Curr Opin Immunol. 2022; 74: 133-139Crossref Scopus (1) Google Scholar,3Hammad H. Lambrecht B.N. The basic immunology of asthma.Cell. 2021; 184: 1469-1485Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar,7Berin M.C. Agashe C. Burks A.W. Chiang D. Davidson W.F. Dawson P. et al.Allergen-specific T cells and clinical features of food allergy: lessons from CoFAR immunotherapy cohorts.J Allergy Clin Immunol. 2022; 149: 1373-1382.e12Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,10Bertschi N.L. Bazzini C. Schlapbach C. The concept of pathogenic TH2 cells: Collegium Internationale Allergologicum update 2021.Int Arch Allergy Immunol. 2021; 182: 365-380Crossref PubMed Scopus (2) Google Scholar For example, TFH cells induced by allergens are heterogenous, and a specific subset of TFH cells, namely, TFH13 cells that coexpresses the cytokines IL-4 and IL-13, has been shown to be required for anaphylactic IgE induction in response to allergens.1Gowthaman U. Sikder S. Lee D. Fisher C. T follicular helper cells in IgE-mediated pathologies.Curr Opin Immunol. 2022; 74: 133-139Crossref Scopus (1) Google Scholar,2Keet C.A. Berin M.C. The year in food allergy.J Allergy Clin Immunol. 2022; 149: 867-873Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Similarly, TH2 effector cells at the barrier tissue are also very heterogeneous. Although a common IL-4, IL-13, and IL-5 TH2 cytokine signature is found in these cells, the extent of pathogenicity or tissue remodeling seems to be determined by their ability to make additional cytokines such as IL-9, IL-17, IL-10, and IL-31.3Hammad H. Lambrecht B.N. The basic immunology of asthma.Cell. 2021; 184: 1469-1485Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar,10Bertschi N.L. Bazzini C. Schlapbach C. The concept of pathogenic TH2 cells: Collegium Internationale Allergologicum update 2021.Int Arch Allergy Immunol. 2021; 182: 365-380Crossref PubMed Scopus (2) Google Scholar For example, in asthma, TH2 effector cells that also express IL-9 or IL-17 are likely to be severely pathologic.3Hammad H. Lambrecht B.N. The basic immunology of asthma.Cell. 2021; 184: 1469-1485Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar Likewise in AD, an IL-31–producing TH2 cell population seems to drive itch, barrier disruption, and the associated inflammatory response.9Haddad E.-B. Cyr S.L. Arima K. McDonald R.A. Levit N.A. Nestle F.O. Current and emerging strategies to inhibit type 2 inflammation in atopic dermatitis.Dermatol Ther (Heidelb). 2022; 12: 1501-1533Crossref PubMed Scopus (1) Google ScholarIn conclusion, research in the past decade has unveiled a fundamental dichotomy between TFH and TH2 effector cell subsets in mediating IgE antibody–centric versus cell-mediated inflammation in allergic responses, respectively. In addition, high-throughput approaches, such as single-cell RNA sequencing, and functional studies have revealed an underlying heterogeneity within TH2 effector cells and TFH cell compartments that could contribute to specific type 2 disease states. Thus, there may not be the “garden variety” or “archetypal” type 2 T cell that drives the entire plethora of type 2 disease states; rather, the combination of elicited TH2 effector and TFH subsets may determine the severity and characteristics of specific type 2 disease states or their endotypes. As trials with biologics over the past 2 decades have shown that there may not be a single “magic bullet” to cure all type 2 diseases, understanding the cellular heterogeneity in specific disease states is thus particularly important for designing future immunotherapies. Indeed, strategies that define the cellular context for specific inflammatory modules using multi-omics analysis and systems biology integrated with clinical characteristics and animal model validation could herald a new era for targeted therapies for type 2 disease endotypes and possibly take us a step closer toward personalized medicine. Sensitization to environmental and food antigens leading to hyperresponsive type 2 immune responses have increased to alarming proportions and results in various diseases, including asthma, food allergy (FA), and atopic dermatitis (AD). The pathophysiologic mechanisms of type 2 allergic diseases involve both antibody-mediated (IgE isotype) and type 2 TH cell–mediated mechanisms that drive inflammation.1Gowthaman U. Sikder S. Lee D. Fisher C. T follicular helper cells in IgE-mediated pathologies.Curr Opin Immunol. 2022; 74: 133-139Crossref Scopus (1) Google Scholar The IgE isotype has always been linked to atopy, allergy, and asthma, as it provides a mechanistic link for allergen recognition and the effector functions of mast cells and basophils following allergen exposure.1Gowthaman U. Sikder S. Lee D. Fisher C. T follicular helper cells in IgE-mediated pathologies.Curr Opin Immunol. 2022; 74: 133-139Crossref Scopus (1) Google Scholar Historically, TH2 effector cells were considered to be the sole T-cell subset that could mediate all manifestations of allergic disease, including helping B cells make IgE antibodies as well as cell-mediated tissue inflammation. However, this notion has been changing lately, as a distinct subset of CD4 T cells called T follicular helper (TFH) cells were identified as dedicated helpers of B cells, helping them to drive antibody production, including IgE, in many type 2 disease models.1Gowthaman U. Sikder S. Lee D. Fisher C. T follicular helper cells in IgE-mediated pathologies.Curr Opin Immunol. 2022; 74: 133-139Crossref Scopus (1) Google Scholar,2Keet C.A. Berin M.C. The year in food allergy.J Allergy Clin Immunol. 2022; 149: 867-873Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Although both TFH and TH2 effector cells can express the IgE switch factor IL-4, TFH cells are distinct from TH2 effector cells owing to their unique ability to home to B-cell areas and promote class-switching and antibody affinity maturation. Thus, a functional dichotomy between TH2 effector cells directly modulating inflammation in tissues and TFH cells in secondary lymphoid organs regulating peripheral inflammation via IgE modulation has begun to emerge. With this distinction, a fresh look at type 2 diseases reveals both distinct and collective roles for TH2 effector cells and TFH cells in dictating type 2 disease states (Fig 1). Allergic diseases, TH2 effector cells, and TFH cellsAllergic diseases often manifest at barrier sites such as the lung, gut, and skin. Asthma remains one of the most prevalent allergic diseases. Asthma can be broadly categorized as type 2high (or T2) and type 2low asthma. T2 asthma is the most prevalent type of asthma and is driven by aberrant type 2 responses such as the accumulation of TH2 effector cells, eosinophils, and group 2 innate lymphoid cells (ILC2s) in the lung.3Hammad H. Lambrecht B.N. The basic immunology of asthma.Cell. 2021; 184: 1469-1485Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar,4Ray A. Camiolo M. Fitzpatrick A. Gauthier M. Wenzel S.E. Are we meeting the promise of endotypes and precision medicine in asthma?.Physiol Rev. 2020; 100: 983-1017Crossref PubMed Scopus (37) Google Scholar In contrast, type 2low asthma is mediated by the infiltration of neutrophils in the lung. Both IgE-associated and IgE-independent T2 asthma endotypes exist in humans.4Ray A. Camiolo M. Fitzpatrick A. Gauthier M. Wenzel S.E. Are we meeting the promise of endotypes and precision medicine in asthma?.Physiol Rev. 2020; 100: 983-1017Crossref PubMed Scopus (37) Google Scholar However, mouse studies have shown that many of the asthma clinical features could be replicated independently of IgE or TFH cells, and thus the disease seems to be predominantly TH2 effector cell–mediated.1Gowthaman U. Sikder S. Lee D. Fisher C. T follicular helper cells in IgE-mediated pathologies.Curr Opin Immunol. 2022; 74: 133-139Crossref Scopus (1) Google Scholar,4Ray A. Camiolo M. Fitzpatrick A. Gauthier M. Wenzel S.E. Are we meeting the promise of endotypes and precision medicine in asthma?.Physiol Rev. 2020; 100: 983-1017Crossref PubMed Scopus (37) Google Scholar Although TFH cells have been shown to convert to TH2 effector cells, the conversion may not be an absolute necessity, as mouse models of asthma with T-cell–specific deletion of Bcl6, which abrogates TFH cell development, have intact TH2 cell induction and lung inflammation, including eosinophilia.1Gowthaman U. Sikder S. Lee D. Fisher C. T follicular helper cells in IgE-mediated pathologies.Curr Opin Immunol. 2022; 74: 133-139Crossref Scopus (1) Google Scholar,5He K. Hettinga A. Kale S.L. Hu S. Xie M.M. Dent A.L. et al.Blimp-1 is essential for allergen-induced asthma and Th2 cell development in the lung.J Exp Med. 2020; : 217Google Scholar Conversely, in mouse models of T-cell–specific Blimp1 deletion, the development TH2 effector cells, but not TFH cells and IgE, is abrogated, which results in protection against eosinophilia and airway hyperresponsiveness to airway allergens.5He K. Hettinga A. Kale S.L. Hu S. Xie M.M. Dent A.L. et al.Blimp-1 is essential for allergen-induced asthma and Th2 cell development in the lung.J Exp Med. 2020; : 217Google Scholar Nevertheless, IgE antibodies may act as amplifiers of the disease, as anti-IgE therapy has some beneficial effects in some patients, and adoptive transfer of IgE in mice and subsequent challenge result in asthma-like symptoms.1Gowthaman U. Sikder S. Lee D. Fisher C. T follicular helper cells in IgE-mediated pathologies.Curr Opin Immunol. 2022; 74: 133-139Crossref Scopus (1) Google Scholar,3Hammad H. Lambrecht B.N. The basic immunology of asthma.Cell. 2021; 184: 1469-1485Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar,4Ray A. Camiolo M. Fitzpatrick A. Gauthier M. Wenzel S.E. Are we meeting the promise of endotypes and precision medicine in asthma?.Physiol Rev. 2020; 100: 983-1017Crossref PubMed Scopus (37) Google ScholarAllergic response to food is the immune-mediated adverse reaction that occurs reproducibly following exposure to a particular food. The allergic response to food ranges from immediate hypersensitivity reactions (including anaphylactic response) occurring within minutes to hours of exposure to a chronic inflammatory response such as that in eosinophilic esophagitis (EoE).2Keet C.A. Berin M.C. The year in food allergy.J Allergy Clin Immunol. 2022; 149: 867-873Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,6Hill D.A. Spergel J.M. The immunologic mechanisms of eosinophilic esophagitis.Curr Allergy Asthma Rep. 2016; 16: 1-15Crossref Scopus (40) Google Scholar The immediate anaphylactic response to food antigens is primarily IgE dependent and thus likely TFH cell–dependent. Indeed, genetic mouse models that specifically lack TFH cells show severely impaired IgE elicitation as well as anaphylaxis in response to food allergens.1Gowthaman U. Sikder S. Lee D. Fisher C. T follicular helper cells in IgE-mediated pathologies.Curr Opin Immunol. 2022; 74: 133-139Crossref Scopus (1) Google Scholar,2Keet C.A. Berin M.C. The year in food allergy.J Allergy Clin Immunol. 2022; 149: 867-873Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Although it could be hypothesized that IgE responses to food allergens are also TFH cell–dependent in humans, a distinctive population of circulating TH2 cells (TH2A cells) have been identified in patients with FA.7Berin M.C. Agashe C. Burks A.W. Chiang D. Davidson W.F. Dawson P. et al.Allergen-specific T cells and clinical features of food allergy: lessons from CoFAR immunotherapy cohorts.J Allergy Clin Immunol. 2022; 149: 1373-1382.e12Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Whether these cells are related to TFH cells and whether they affect food-specific IgE remains unclear. In contrast to what occurs in FA, in EoE, the primary disease mechanism seems to be non–IgE-mediated eosinophilic infiltration of the esophagus despite the disease presenting itself with comorbid allergic conditions, including asthma and IgE-mediated FA.6Hill D.A. Spergel J.M. The immunologic mechanisms of eosinophilic esophagitis.Curr Allergy Asthma Rep. 2016; 16: 1-15Crossref Scopus (40) Google Scholar Indeed, anti-IgE therapy (omalizumab) does not seem to have any benefit in EoE; however, it has shown some promising results in patients with FA, especially in conjunction with oral immunotherapy.2Keet C.A. Berin M.C. The year in food allergy.J Allergy Clin Immunol. 2022; 149: 867-873Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Thus, it is likely that the key drivers of eosinophilic infiltration in EoE are TH2 effector cells and ILC2s. Whether EoE can be induced in mouse models that specifically lack TFH cells remains underexplored.Yet another major type 2 inflammatory disease is AD, in which the skin is the major barrier site affected. AD is often triggered by barrier dysfunction followed by skin dysbiosis and environmental allergen exposure, and it is typified by pruritus and inflammatory skin lesions.8Czarnowicki T. He H. Krueger J.G. Guttman-Yassky E. Atopic dermatitis endotypes and implications for targeted therapeutics.J Allergy Clin Immunol. 2019; 143: 1-11Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar Although high IgE levels are often associated with AD, especially in the extrinsic type affecting the majority of people, IgE does not seem to be the main driver of the disease.8Czarnowicki T. He H. Krueger J.G. Guttman-Yassky E. Atopic dermatitis endotypes and implications for targeted therapeutics.J Allergy Clin Immunol. 2019; 143: 1-11Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar Indeed, AD can be induced in mouse models independently of IgE, and anti-IgE therapy in patients has not had a significant effect and is not indicated as a therapy for AD.8Czarnowicki T. He H. Krueger J.G. Guttman-Yassky E. Atopic dermatitis endotypes and implications for targeted therapeutics.J Allergy Clin Immunol. 2019; 143: 1-11Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar,9Haddad E.-B. Cyr S.L. Arima K. McDonald R.A. Levit N.A. Nestle F.O. Current and emerging strategies to inhibit type 2 inflammation in atopic dermatitis.Dermatol Ther (Heidelb)