TFH cells regulate antibody affinity and determine the outcomes of anaphylaxis

Abstract

The immunologic mechanism of food allergy and anaphylaxis is not fully understood, although allergen-specific IgE antibodies are considered a main driver of anaphylaxis. However, not all individuals who have allergen-specific IgE experience allergic reactions when exposed to the allergen to which they are sensitized. Conversely, some patients experience anaphylaxis despite having low or undetectable levels of allergen-specific IgE.1Simons F.E. Frew A.J. Ansotegui I.J. Bochner B.S. Golden D.B. Finkelman F.D. et al.Risk assessment in anaphylaxis: current and future approaches.J Allergy Clin Immunol. 2007; 120: S2-S24Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar Several possible explanations can be considered to explain the lack of direct relationship. For example, the ratio of allergen-specific IgE to total IgE may determine the threshold for clinical reactivity. Characteristics of allergen-specific IgE antibodies, such as glycosylation state and antigen epitopes and affinity, and involvement of allergen-specific non-IgE antibodies are also possible explanations.In IgG antibodies, Fc domain sialyation triggers conformational changes that allow IgG to interact avidly with type II FcγRs and produce anti-inflammatory activity, whereas fucosylation promotes IgG binding to type I FcγRs and proinflammatory activity. Glycosylation may also affect the biologic activities of IgE. A single glycan that is critical for anaphylaxis was identified in constant domain 3 of IgE. Genetic disruption of this site or enzymatic removal of the glycan altered the structure of IgE, making it incapable of binding to FcεRI and causing anaphylaxis. In addition, individuals with peanut allergy produce allergen-specific IgE enriched for sialic acid, which is critical for triggering mast cell activation.2Shade K.C. Conroy M.E. Washburn N. Kitaoka M. Huynh D.J. Laprise E. et al.Sialylation of immunoglobulin E is a determinant of allergic pathogenicity.Nature. 2020; 582: 265-270Crossref PubMed Scopus (54) Google Scholar Although the molecular mechanisms involved in glycosylation of IgE are unknown, IgG Fc sialylation is regulated during the germinal center (GC) reaction by the production of GC B cells that express distinct levels of 2,6-sialytransferase.3Bartsch Y.C. Eschweiler S. Leliavski A. Lunding H.B. Wagt S. Petry J. et al.IgG Fc sialylation is regulated during the germinal center reaction following immunization with different adjuvants.J Allergy Clin Immunol. 2020; 146: 652-666.e11Abstract Full Text Full Text PDF PubMed Scopus (19) Google ScholarEpitopes and affinities of allergen-specific antibodies may also play a major role. Subjects with milk allergy exhibit greater epitope diversity than do those who have outgrown the allergy.4Wang J. Lin J. Bardina L. Goldis M. Nowak-Wegrzyn A. Shreffler W.G. et al.Correlation of IgE/IgG4 milk epitopes and affinity of milk-specific IgE antibodies with different phenotypes of clinical milk allergy.J Allergy Clin Immunol. 2010; 125: 695-702.e1-.e6Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar Subjects with milk allergy also demonstrate a combination of high- and low-affinity IgE binding, whereas subjects who are tolerant of milk have mainly low-affinity IgE. Similarly, overall IgE affinity for allergens is associated with outcomes of skin prick tests. Although the inability to isolate individual IgE antibodies from patient serum presents a major hurdle to understanding the cause-and-effect relationship between antibody affinity and manifestation of allergic reactions, recent studies in mouse models investigating follicular helper T (TFH) cells have provided some insights in this regard.TFH cells, a specialized subset of T cells that provide help to B cells, are essential for GC formation and development of high-affinity antibodies.5Crotty S.T. Follicular helper cell biology: a decade of discovery and diseases.Immunity. 2019; 50: 1132-1148Abstract Full Text Full Text PDF PubMed Scopus (517) Google Scholar TFH cells are necessary and sufficient for production of IgE antibodies,6Kobayashi T. Iijima K. Dent A.L. Kita H. Follicular helper T cells mediate IgE antibody response to airborne allergens.J Allergy Clin Immunol. 2017; 139: 300-313.e7Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar and they are indispensable for the manifestation of acute anaphylaxis in response to environmental allergens in a mouse model of peanut allergy. In GCs, B cells circulate through the light zone and dark zone. In the light zone, TFH cells provide signals that promote the survival and proliferation of GC B cells. In the dark zone, GC B cells undergo proliferation and somatic hypermutation; in the light zone, B cells with the highest affinity to an antigen are selected by TFH cells for further proliferation and maturation. Affinity maturation of GC B cells depends on the right amount of “help” provided by TFH cells, such as cytokines (eg, IL-4, IL-21) and direct cellular interactions.5Crotty S.T. Follicular helper cell biology: a decade of discovery and diseases.Immunity. 2019; 50: 1132-1148Abstract Full Text Full Text PDF PubMed Scopus (517) Google ScholarAlthough IL-4 has long been recognized to induce IgE class switching, it is likely insufficient to induce production of high-affinity IgE. A subset of TFH cells (ie, TFH13 cells) that produce IL-13 in addition to IL-4 was recently identified (Fig 1).7Gowthaman U. Chen J.S. Zhang B. Flynn W.F. Lu Y. Song W. et al.Identification of a T follicular helper cell subset that drives anaphylactic IgE.Science. 2019; 365eaaw6433Crossref PubMed Scopus (171) Google Scholar TFH13 cells were shown to develop in lung-draining lymph nodes when naive mice were exposed intranasally to extracts of the fungus Alternaria or house dust mites. Loss of Il13 in TFH cells resulted in reduced production of high-affinity IgE and protected the host from anaphylaxis, whereas modest effects were observed in terms of the levels of total or low-affinity IgE.7Gowthaman U. Chen J.S. Zhang B. Flynn W.F. Lu Y. Song W. et al.Identification of a T follicular helper cell subset that drives anaphylactic IgE.Science. 2019; 365eaaw6433Crossref PubMed Scopus (171) Google Scholar Interestingly, infection with the helminth Nippostrongylus brasiliensis produced conventional TFH cells and low-affinity IgE but failed to produce TFH13 cells or high-affinity IgE, consistent with clinical findings in which IgE exhibiting little affinity maturation was found in individuals living in an area of endemic parasitism. Peanut-specific TFH13 cells were also identified in the peripheral blood of patients with peanut allergies. Although the mechanism by which IL-13, as compared with the canonic cytokine IL-4, modulates TFH and B-cell interactions and promotes affinity maturation of IgE is not fully understood, this study elucidated the critical role of the affinity of allergen-specific antibodies, and not simply their quantity, in determining clinical manifestations of allergic reactions.Physical interactions between TFH cells and GC B cells likely play a pivotal role in affinity maturation as well (Fig 1). For example, negative signaling through cell surface SLAMF6 limits TFH cell help, thereby enhancing selective pressure and promoting selection of B cells that produce high-affinity antibodies. In addition to SLAMF6, TFH cells express multiple inhibitory receptors, which may control TFH and GC B-cell interactions and affect the resulting antibody quality. Programmed cell death protein 1 (PD-1) is highly expressed on TFH cells, and its interaction with programmed death-ligand 1/2 (PD-L1/L2) on GC B cells likely maintains the stringency of affinity selection in the GC. Deletion of PD-1 in antigen-specific TFH cells modulates their positioning in lung-draining lymph nodes and compromises the affinity maturation of GC B cells. In a mouse model of peanut allergy, blockade or deletion of PD-1 in TFH cells increased the numbers of TFH and GC B cells and increased the titers of peanut-specific IgG while decreasing the levels of IgE.8Lama J.K. Iijima K. Kobayashi T. Kita H. Blocking the inhibitory receptor programmed cell death 1 prevents allergic immune response and anaphylaxis in mice.J Allergy Clin Immunol. 2022; 150: 178-191Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar The affinity of peanut-specific IgG in anti–PD-1–treated mice was significantly lower than that of mice treated with control antibody. These low-affinity antibodies were unable to trigger an anaphylactic reaction when transferred to recipients and instead protected the recipients from developing anaphylaxis when they were challenged with a peanut allergen.8Lama J.K. Iijima K. Kobayashi T. Kita H. Blocking the inhibitory receptor programmed cell death 1 prevents allergic immune response and anaphylaxis in mice.J Allergy Clin Immunol. 2022; 150: 178-191Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar PD-1 also reduces the positive feedback between TFH cells and B cells mediated by the inducible costimulatory molecule (ICOS)–inducible costimulatory molecule ligand (ICOSL) interaction, thereby enforcing a more stringent selection of B cells. Further research into the molecular and cellular mechanisms by which PD-1 and other inhibitory receptors on TFH cells act as a checkpoint to regulate antibody production and affinity maturation will likely provide insights into the mechanisms of allergic diseases.Lastly, the potential roles of non-IgE antibodies may need to be considered to explain anaphylaxis in subjects who have undetectable levels of allergen-specific IgE. Several mouse model studies have shown that allergen-specific IgG can induce systemic anaphylaxis with clinical manifestations similar to those seen in patients with IgE-mediated anaphylaxis.9Finkelman F.D. Khodoun M.V. Strait R. Human IgE-independent systemic anaphylaxis.J Allergy Clin Immunol. 2016; 137: 1674-1680Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar Although IgG-dependent anaphylaxis in humans remains controversial, drug-induced anaphylaxis appears to be dependent on IgG.10Jönsson F. de Chaisemartin L. Granger V. Gouel-Chéron A. Gillis C.M. Zhu Q. et al.An IgG-induced neutrophil activation pathway contributes to human drug-induced anaphylaxis.Sci Transl Med. 2019; 11: aat1479Crossref Scopus (61) Google Scholar A recent mouse model study of peanut allergy demonstrated the roles of high-affinity peanut-specific IgG in mediating cutaneous and systemic anaphylaxis in response to intravenous and intraperitoneal challenge, respectively, through the IgG receptor FcγRIII on mast cells.8Lama J.K. Iijima K. Kobayashi T. Kita H. Blocking the inhibitory receptor programmed cell death 1 prevents allergic immune response and anaphylaxis in mice.J Allergy Clin Immunol. 2022; 150: 178-191Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Nonetheless, allergen-specific IgG antibodies have been thought to inhibit IgE-mediated anaphylaxis in response to ingested allergens by blocking their epitopes and engaging the inhibitory IgG receptor FcγRIIb in both animal models and clinical studies. In addition, IgG-mediated anaphylaxis may require a larger dose of antigen than does IgE-mediated anaphylaxis.In summary, conventional belief relies on existing knowledge that TH2 cells mediate IgE antibody production. Indeed, when transferred to T-cell–deficient mice, both TH2 cells and TFH cells promote IgE antibody production, although the effects of TFH cells are more robust and prolonged than those of TH2 cells.6Kobayashi T. Iijima K. Dent A.L. Kita H. Follicular helper T cells mediate IgE antibody response to airborne allergens.J Allergy Clin Immunol. 2017; 139: 300-313.e7Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar However, TH2 cells may contribute to total IgE or low-affinity IgE production, but whether they contribute to the production of high-affinity antibodies is questionable. In contrast, TFH cells likely play a critical role in the production of high-affinity antibodies that react avidly with specific allergens and mediate mast cell activation and anaphylaxis (Fig 1).7Gowthaman U. Chen J.S. Zhang B. Flynn W.F. Lu Y. Song W. et al.Identification of a T follicular helper cell subset that drives anaphylactic IgE.Science. 2019; 365eaaw6433Crossref PubMed Scopus (171) Google Scholar,8Lama J.K. Iijima K. Kobayashi T. Kita H. Blocking the inhibitory receptor programmed cell death 1 prevents allergic immune response and anaphylaxis in mice.J Allergy Clin Immunol. 2022; 150: 178-191Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Therefore, further studies to elucidate the roles of TFH cells in allergic immune responses will expand our understanding of the pathophysiology of allergic diseases and facilitate development of new therapeutic strategies. For example, are TFH13 cells necessary to produce high-affinity IgE, or can conventional TFH (ie, non–IL-13–producing) cells promote production of high-affinity IgE or IgG if they are functionally optimized (ie, characterized by high expression of PD-1)? How can we regulate TFH cells to prevent the development of allergic diseases? How can the TFH cell response be modified to shift away from IgE antibody production or to promote production of low-affinity or even protective allergen-specific antibodies? In addition, the potential roles of high-affinity IgG in mediating anaphylaxis in humans need to be revisited. Recognizing the unique functions of TFH cells that promote B-cell proliferation and affinity maturation and optimize the qualities of antibodies may solve many mysteries associated with allergies. The immunologic mechanism of food allergy and anaphylaxis is not fully understood, although allergen-specific IgE antibodies are considered a main driver of anaphylaxis. However, not all individuals who have allergen-specific IgE experience allergic reactions when exposed to the allergen to which they are sensitized. Conversely, some patients experience anaphylaxis despite having low or undetectable levels of allergen-specific IgE.1Simons F.E. Frew A.J. Ansotegui I.J. Bochner B.S. Golden D.B. Finkelman F.D. et al.Risk assessment in anaphylaxis: current and future approaches.J Allergy Clin Immunol. 2007; 120: S2-S24Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar Several possible explanations can be considered to explain the lack of direct relationship. For example, the ratio of allergen-specific IgE to total IgE may determine the threshold for clinical reactivity. Characteristics of allergen-specific IgE antibodies, such as glycosylation state and antigen epitopes and affinity, and involvement of allergen-specific non-IgE antibodies are also possible explanations. In IgG antibodies, Fc domain sialyation triggers conformational changes that allow IgG to interact avidly with type II FcγRs and produce anti-inflammatory activity, whereas fucosylation promotes IgG binding to type I FcγRs and proinflammatory activity. Glycosylation may also affect the biologic activities of IgE. A single glycan that is critical for anaphylaxis was identified in constant domain 3 of IgE. Genetic disruption of this site or enzymatic removal of the glycan altered the structure of IgE, making it incapable of binding to FcεRI and causing anaphylaxis. In addition, individuals with peanut allergy produce allergen-specific IgE enriched for sialic acid, which is critical for triggering mast cell activation.2Shade K.C. Conroy M.E. Washburn N. Kitaoka M. Huynh D.J. Laprise E. et al.Sialylation of immunoglobulin E is a determinant of allergic pathogenicity.Nature. 2020; 582: 265-270Crossref PubMed Scopus (54) Google Scholar Although the molecular mechanisms involved in glycosylation of IgE are unknown, IgG Fc sialylation is regulated during the germinal center (GC) reaction by the production of GC B cells that express distinct levels of 2,6-sialytransferase.3Bartsch Y.C. Eschweiler S. Leliavski A. Lunding H.B. Wagt S. Petry J. et al.IgG Fc sialylation is regulated during the germinal center reaction following immunization with different adjuvants.J Allergy Clin Immunol. 2020; 146: 652-666.e11Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Epitopes and affinities of allergen-specific antibodies may also play a major role. Subjects with milk allergy exhibit greater epitope diversity than do those who have outgrown the allergy.4Wang J. Lin J. Bardina L. Goldis M. Nowak-Wegrzyn A. Shreffler W.G. et al.Correlation of IgE/IgG4 milk epitopes and affinity of milk-specific IgE antibodies with different phenotypes of clinical milk allergy.J Allergy Clin Immunol. 2010; 125: 695-702.e1-.e6Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar Subjects with milk allergy also demonstrate a combination of high- and low-affinity IgE binding, whereas subjects who are tolerant of milk have mainly low-affinity IgE. Similarly, overall IgE affinity for allergens is associated with outcomes of skin prick tests. Although the inability to isolate individual IgE antibodies from patient serum presents a major hurdle to understanding the cause-and-effect relationship between antibody affinity and manifestation of allergic reactions, recent studies in mouse models investigating follicular helper T (TFH) cells have provided some insights in this regard. TFH cells, a specialized subset of T cells that provide help to B cells, are essential for GC formation and development of high-affinity antibodies.5Crotty S.T. Follicular helper cell biology: a decade of discovery and diseases.Immunity. 2019; 50: 1132-1148Abstract Full Text Full Text PDF PubMed Scopus (517) Google Scholar TFH cells are necessary and sufficient for production of IgE antibodies,6Kobayashi T. Iijima K. Dent A.L. Kita H. Follicular helper T cells mediate IgE antibody response to airborne allergens.J Allergy Clin Immunol. 2017; 139: 300-313.e7Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar and they are indispensable for the manifestation of acute anaphylaxis in response to environmental allergens in a mouse model of peanut allergy. In GCs, B cells circulate through the light zone and dark zone. In the light zone, TFH cells provide signals that promote the survival and proliferation of GC B cells. In the dark zone, GC B cells undergo proliferation and somatic hypermutation; in the light zone, B cells with the highest affinity to an antigen are selected by TFH cells for further proliferation and maturation. Affinity maturation of GC B cells depends on the right amount of “help” provided by TFH cells, such as cytokines (eg, IL-4, IL-21) and direct cellular interactions.5Crotty S.T. Follicular helper cell biology: a decade of discovery and diseases.Immunity. 2019; 50: 1132-1148Abstract Full Text Full Text PDF PubMed Scopus (517) Google Scholar Although IL-4 has long been recognized to induce IgE class switching, it is likely insufficient to induce production of high-affinity IgE. A subset of TFH cells (ie, TFH13 cells) that produce IL-13 in addition to IL-4 was recently identified (Fig 1).7Gowthaman U. Chen J.S. Zhang B. Flynn W.F. Lu Y. Song W. et al.Identification of a T follicular helper cell subset that drives anaphylactic IgE.Science. 2019; 365eaaw6433Crossref PubMed Scopus (171) Google Scholar TFH13 cells were shown to develop in lung-draining lymph nodes when naive mice were exposed intranasally to extracts of the fungus Alternaria or house dust mites. Loss of Il13 in TFH cells resulted in reduced production of high-affinity IgE and protected the host from anaphylaxis, whereas modest effects were observed in terms of the levels of total or low-affinity IgE.7Gowthaman U. Chen J.S. Zhang B. Flynn W.F. Lu Y. Song W. et al.Identification of a T follicular helper cell subset that drives anaphylactic IgE.Science. 2019; 365eaaw6433Crossref PubMed Scopus (171) Google Scholar Interestingly, infection with the helminth Nippostrongylus brasiliensis produced conventional TFH cells and low-affinity IgE but failed to produce TFH13 cells or high-affinity IgE, consistent with clinical findings in which IgE exhibiting little affinity maturation was found in individuals living in an area of endemic parasitism. Peanut-specific TFH13 cells were also identified in the peripheral blood of patients with peanut allergies. Although the mechanism by which IL-13, as compared with the canonic cytokine IL-4, modulates TFH and B-cell interactions and promotes affinity maturation of IgE is not fully understood, this study elucidated the critical role of the affinity of allergen-specific antibodies, and not simply their quantity, in determining clinical manifestations of allergic reactions. Physical interactions between TFH cells and GC B cells likely play a pivotal role in affinity maturation as well (Fig 1). For example, negative signaling through cell surface SLAMF6 limits TFH cell help, thereby enhancing selective pressure and promoting selection of B cells that produce high-affinity antibodies. In addition to SLAMF6, TFH cells express multiple inhibitory receptors, which may control TFH and GC B-cell interactions and affect the resulting antibody quality. Programmed cell death protein 1 (PD-1) is highly expressed on TFH cells, and its interaction with programmed death-ligand 1/2 (PD-L1/L2) on GC B cells likely maintains the stringency of affinity selection in the GC. Deletion of PD-1 in antigen-specific TFH cells modulates their positioning in lung-draining lymph nodes and compromises the affinity maturation of GC B cells. In a mouse model of peanut allergy, blockade or deletion of PD-1 in TFH cells increased the numbers of TFH and GC B cells and increased the titers of peanut-specific IgG while decreasing the levels of IgE.8Lama J.K. Iijima K. Kobayashi T. Kita H. Blocking the inhibitory receptor programmed cell death 1 prevents allergic immune response and anaphylaxis in mice.J Allergy Clin Immunol. 2022; 150: 178-191Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar The affinity of peanut-specific IgG in anti–PD-1–treated mice was significantly lower than that of mice treated with control antibody. These low-affinity antibodies were unable to trigger an anaphylactic reaction when transferred to recipients and instead protected the recipients from developing anaphylaxis when they were challenged with a peanut allergen.8Lama J.K. Iijima K. Kobayashi T. Kita H. Blocking the inhibitory receptor programmed cell death 1 prevents allergic immune response and anaphylaxis in mice.J Allergy Clin Immunol. 2022; 150: 178-191Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar PD-1 also reduces the positive feedback between TFH cells and B cells mediated by the inducible costimulatory molecule (ICOS)–inducible costimulatory molecule ligand (ICOSL) interaction, thereby enforcing a more stringent selection of B cells. Further research into the molecular and cellular mechanisms by which PD-1 and other inhibitory receptors on TFH cells act as a checkpoint to regulate antibody production and affinity maturation will likely provide insights into the mechanisms of allergic diseases. Lastly, the potential roles of non-IgE antibodies may need to be considered to explain anaphylaxis in subjects who have undetectable levels of allergen-specific IgE. Several mouse model studies have shown that allergen-specific IgG can induce systemic anaphylaxis with clinical manifestations similar to those seen in patients with IgE-mediated anaphylaxis.9Finkelman F.D. Khodoun M.V. Strait R. Human IgE-independent systemic anaphylaxis.J Allergy Clin Immunol. 2016; 137: 1674-1680Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar Although IgG-dependent anaphylaxis in humans remains controversial, drug-induced anaphylaxis appears to be dependent on IgG.10Jönsson F. de Chaisemartin L. Granger V. Gouel-Chéron A. Gillis C.M. Zhu Q. et al.An IgG-induced neutrophil activation pathway contributes to human drug-induced anaphylaxis.Sci Transl Med. 2019; 11: aat1479Crossref Scopus (61) Google Scholar A recent mouse model study of peanut allergy demonstrated the roles of high-affinity peanut-specific IgG in mediating cutaneous and systemic anaphylaxis in response to intravenous and intraperitoneal challenge, respectively, through the IgG receptor FcγRIII on mast cells.8Lama J.K. Iijima K. Kobayashi T. Kita H. Blocking the inhibitory receptor programmed cell death 1 prevents allergic immune response and anaphylaxis in mice.J Allergy Clin Immunol. 2022; 150: 178-191Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Nonetheless, allergen-specific IgG antibodies have been thought to inhibit IgE-mediated anaphylaxis in response to ingested allergens by blocking their epitopes and engaging the inhibitory IgG receptor FcγRIIb in both animal models and clinical studies. In addition, IgG-mediated anaphylaxis may require a larger dose of antigen than does IgE-mediated anaphylaxis. In summary, conventional belief relies on existing knowledge that TH2 cells mediate IgE antibody production. Indeed, when transferred to T-cell–deficient mice, both TH2 cells and TFH cells promote IgE antibody production, although the effects of TFH cells are more robust and prolonged than those of TH2 cells.6Kobayashi T. Iijima K. Dent A.L. Kita H. Follicular helper T cells mediate IgE antibody response to airborne allergens.J Allergy Clin Immunol. 2017; 139: 300-313.e7Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar However, TH2 cells may contribute to total IgE or low-affinity IgE production, but whether they contribute to the production of high-affinity antibodies is questionable. In contrast, TFH cells likely play a critical role in the production of high-affinity antibodies that react avidly with specific allergens and mediate mast cell activation and anaphylaxis (Fig 1).7Gowthaman U. Chen J.S. Zhang B. Flynn W.F. Lu Y. Song W. et al.Identification of a T follicular helper cell subset that drives anaphylactic IgE.Science. 2019; 365eaaw6433Crossref PubMed Scopus (171) Google Scholar,8Lama J.K. Iijima K. Kobayashi T. Kita H. Blocking the inhibitory receptor programmed cell death 1 prevents allergic immune response and anaphylaxis in mice.J Allergy Clin Immunol. 2022; 150: 178-191Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Therefore, further studies to elucidate the roles of TFH cells in allergic immune responses will expand our understanding of the pathophysiology of allergic diseases and facilitate development of new therapeutic strategies. For example, are TFH13 cells necessary to produce high-affinity IgE, or can conventional TFH (ie, non–IL-13–producing) cells promote production of high-affinity IgE or IgG if they are functionally optimized (ie, characterized by high expression of PD-1)? How can we regulate TFH cells to prevent the development of allergic diseases? How can the TFH cell response be modified to shift away from IgE antibody production or to promote production of low-affinity or even protective allergen-specific antibodies? In addition, the potential roles of high-affinity IgG in mediating anaphylaxis in humans need to be revisited. Recognizing the unique functions of TFH cells that promote B-cell proliferation and affinity maturation and optimize the qualities of antibodies may solve many mysteries associated with allergies.