Allergy encompasses a complex array of diseases that combine innate and 33adaptive immunity, host genetic polymorphisms, and environmental triggers that collectively influence susceptibility to type 2 inflammation. Skin barrier dysfunction in the setting of atopic dermatitis (AD) leads to cutaneous allergen sensitization. The atopic march hypothesis proposes that skin sensiti-zation leads to the subsequent hypersensitivity to allergens at other barrier sur-faces, resulting in asthma, food allergy, and its associated anaphylaxis. However, the mechanisms by which local sensitization to antigens in the skin promotes widespread humoral allergic immune responses via memory T cell generation remain poorly defined.In the last three years, we have tried to understand the role of IL-13 in local priming in the skin and the resulting systemic anaphylaxis. We have been using the cutaneous allergen sensitization mouse model with a vitamin D3 analog Calcipotriol, MC903. Deficiency of Il13 or Il13ra1 in dendritic cells (DCs) at-tenuated the high-affinity IgE responses and anaphylaxis. Accumulation of CX3CR1+CD11bmid type 2 conventional DC (cDC2s) expressing the IL-13 receptor (IL-13R) in the secondary allergen entry site, the spleen, is critical for the T follicular helper (TFH) memory responses reacting to skin-sensitized allergens. In systemic anaphylaxis, the memory Th2 cell-derived IL-13 contrib-uted to the maturation and expansion of MHC class IIhi cDC2s. These cells are responsible for the high-affinity IgE response via efficiently generating allergen-specific memory TFH2 cells, which were converted from memory Th2 cells. These findings have important implications for understanding the role of IL-13 signals in cDC2s, connecting skin and distal second lymphoid organs in pro-moting systemic allergic responses.Figure: IL-13 signals in cDC2s connect skin and distal secondary lymphoid organs to promote systemic allergic responsesSkin sensitization promotes the maturation and expan-sion of cDC2 in IgE-mediated allergic responses. The an-tigen information from the skin is first captured by the skin-derived migratory CX3CR1+cDC2s, which migrate to afferent lymph nodes to generate Th2 cells. These activated Th2 cells migrate to distal lymphoid organs, where they remain as memory Th2 cells. In secondary responses, intraperitoneal priming induces CX3CL1 ex-pression in the vascular endothelium cells of the spleen to allow the migratory cDC2s to be attracted to the inflamed spleen. In this scenario, memory T cell-derived IL-13 promoted the maturation and expansion of cDC2s. This process enhances the antigen presentation ability to accelerate TFH2 differentiation, which is necessary for GC-dependent high-affinity IgE production.Recent Major PublicationsPark J, Cho Y, Yang D, Yang H, Lee D, Kubo M, Kang S-J. The transcription factor NFIL3/E4BP4 regulates the developmental stage-specific acquisition of basophil function. J Allergy Clin Immunol 153, 132-145 (2024)Takamura S, Nomura A, Kubo M. BCL6 fine-tunes long-term tumor control. Sci Immunol 8, eadj6724 (2023)Harada Y, Sasaki T, Wibisana J-N, Okada-Hatakeyama M, Ueno H, Burrows PD, Kubo M. Type 2 helper T cells convert to Interleukin-1 13 expressing follicular helper T cells after antigen repriming. Translat Regulat Sci 5, 1-12 (2023)Invited presentationsKubo M. “Role of IL-13 signal in allergic march caused by atopic dermatitis” The 52nd Annual Meeting of the Japanese Society for Immunology (Chiba, Japan) Janu-ary 2024Kubo M. “Role of IL-13 in allergic march” Tongji Medical College Huazhong University of Science Technology (Wuhan, China) December 2023Kubo M. “Mysterious white blood cells, basophils” The 53rd Annual Meeting of the Japanese Society for Cutaneous Immunology and Allergy (Urayasu, Japan) December 2023Kubo M. “Role of interleukin-13 receptor-positive den-dritic cells in connecting multiple organs in allergic re-sponses initiated in the skin” The 72nd Annual Meeting of the Japanese Society of Allergology (Tokyo, Japan) October 2023Laboratory for Cytokine RegulationTeam Leader: Masato Kubo
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