Suppression of Immunotherapy on Group 2 Innate Lymphoid Cells in Allergic Rhinitis

Background： Group 2 innate lymphoid cells （ILC2s） are regarded as a novel population of lineage-negative cells that induce innate Type 2 responses by producing the critical Th2-type cytokines interleukin （IL）-5 and IL-13. ILC2s as key players in the development of allergic rhinitis （AR） have been proved, however, the effect of subcutaneous immunotherapy （SCIT） with dermatophagoides pteronyssinus extract （Der p-SCIT） on ILC2s in AR patients is not clear. This study aimed to investigate the response of ILC2s of peripheral blood in house dust mites （HDM）-sensitized Chinese patients with AR who received SCIT with Der P extract. Methods： Seven healthy controls without symptoms of AR who had negative reactions to any of the allergens from skin-prick testing, nine patients diagnosed with persistent AR according to the Allergic Rhinitis and its Impact on Asthma （ARIA） guidelines, and 24 AR patients who received Der p-SCIT for 1.0-3.5 years were recruited for the study. ILC2s in the peripheral blood were evaluated using flow cytometry. The severity of their symptoms of all participants was rated based on the Total 5 symptom score. Results： Among 40 participants, 9 AR patients were assigned to the untreated group, 24 AR patients receiving Der p-SCIT were assigned to the immunotherapy group, and 7 healthy controls without symptoms of AR were assigned to healthy control group. The mean Total 5 symptom score of immunotherapy group was significantly lower than that of untreated group （4.3 ± 1.4 vs. 10.1 ± 2.5, P 〈 0.001 ）. Similarly, the levels of ILC2s in the peripheral blood ofimmunotherapy group were significantly reduced compared with that in untreated group （P 〈 0.001 ）, but were not significantly different from healthy controls （P = 0.775）. Further subgroup analysis based on the duration of SCIT therapy （ 1.0-2.0 years [SCIT1-2], 2.0-3.0 years [SCIT2_3], and 3.0-3.5 years [SCIT3_3.5]） showed that the percentage of ILC2s was not significantly different between SCIT1-2, SCIT2-3, and SCIT3-3.5 groups （SCIT1-2 vs. SCIT2-3： P = 0.268; SCIT1-2, vs. SCIT3-3.5： P = 0.635; and SCIT, 3 vs. SCIT3-3.5： P = 0.787）. Conclusions： The present study highlighted the suppression ofDer p-SCIT on ILC2s in HDM-AR patients. ILC2s identified in peripheral blood can be used as an effective biomarker for Der p-SCIT.

2型固有淋巴细胞调控因素的研究进展

2型固有淋巴细胞(group 2 innate lymphoid cells,ILC2s)是一群不表达谱系发育因子Lineage,不具有抗原特异性的特殊免疫细胞,能够在IL-33和IL-25的刺激下产生大量IL-5和IL-13,介导2型先天性免疫应答,在变应性和炎症性疾病中发挥重要作用。近年来ILC2s不同细胞亚型以及复杂的调控因子网络逐渐被发现和证实,这些研究结果拓展了对先天性免疫应答的认识,尤其是ILC2s参与变应原或病原体介导的气道炎症反应,为临床治疗提供了新的思路。

Orchestration between ILC2s and Th2 cells in shaping type 2 immune responses

The type 2 immune response is critical for host defense against large parasites such as helminths.On the other hand,dysregulation of the type 2 immune response may cause immunopathological conditions,including asthma,atopic dermatitis,rhinitis,and anaphylaxis.Thus,a balanced type 2 immune response must be achieved to mount effective protection against invading pathogens while avoiding immunopathology.The classical model of type 2 immunity mainly involves the differentiation of type 2 T helper(Th2)cells and the production of distinct type 2 cytokines,including interleukin-4(IL-4),IL-5,and IL-13.Group 2 innate lymphoid cells(ILC2s)were recently recognized as another important source of type 2 cytokines.Although eosinophils,mast cells,and basophils can also express type 2 cytokines and participate in type 2 immune responses to various degrees,the production of type 2 cytokines by the lymphoid lineages,Th2 cells,and ILC2s in particular is the central event during the type 2 immune response.In this review,we discuss recent advances in our understanding of how ILC2s and Th2 cells orchestrate type 2 immune responses through direct and indirect interactions.

HTR2A agonists play a therapeutic role by restricting ILC2 activation in papain-induced lung inflammation

Group 2 innate lymphoid cells(ILC2s)are a category of heterogeneous cells that produce the cytokines IL-5 and IL-13,which mediate the type 2 immune response.However,specific drug targets on lung ILC2s have rarely been reported.Previous studies have shown that type 2 cytokines,such as IL-5 and IL-13,are related to depression.Here,we demonstrated the negative correlation between the depression-associated monoamine neurotransmitter serotonin and secretion of the cytokines IL-5 and IL-13 by ILC2s in individuals with depression.Interestingly,serotonin ameliorates papain-induced lung inflammation by suppressing ILC2 activation.Our data showed that the serotonin receptor HTR2A was highly expressed on ILC2s from mouse lungs and human PBMCs.Furthermore,an HTR2A selective agonist(DOI)impaired ILC2 activation and alleviated the type 2 immune response in vivo and in vitro.Mice with ILC2-specific depletion of HTR2A(Il5^(cre/+)·Htr2a^(flox/flox)mice)abolished the DOI-mediated inhibition of ILC2s in a papain-induced mouse model of inflammation.In conclusion,serotonin and DOI could restrict the type 2 lung immune response,indicating a potential treatment strategy for type 2 lung inflammation by targeting HTR2A on ST2+ILC2s.