{"doi":"10.3389/fimmu.2022.1041552","title":"ICAMs are dispensable for influenza clearance and anti-viral humoral and cellular immunity","abstract":"αLβ2 (LFA-1) mediated interactions with ICAM-1 and ICAM-2 predominate leukocyte-vascular interactions, but their functions in extravascular cell-cell communications is still debated. The roles of these two ligands in leukocyte trafficking, lymphocyte differentiation, and immunity to influenza infections were dissected in the present study. Surprisingly, double ICAM-1 and ICAM-2 knock out mice (herein ICAM-1/2 -/- mice) infected with a lab adapted H1N1 influenza A virus fully recovered from infection, elicited potent humoral immunity, and generated normal long lasting anti-viral CD8 + T cell memory. Furthermore, lung capillary ICAMs were dispensable for both NK and neutrophil entry to virus infected lungs. Mediastinal lymph nodes (MedLNs) of ICAM-1/2 -/- mice poorly recruited naïve T cells and B lymphocytes but elicited normal humoral immunity critical for viral clearance and effective CD8 + differentiation into IFN-γ producing T cells. Furthermore, whereas reduced numbers of virus specific effector CD8 + T cells accumulated inside infected ICAM-1/2 -/- lungs, normal virus-specific T RM CD8 + cells were generated inside these lungs and fully protected ICAM-1/2 -/- mice from secondary heterosubtypic infections. B lymphocyte entry to the MedLNs and differentiation into extrafollicular plasmablasts, producing high affinity anti-influenza IgG2a antibodies, were also ICAM-1 and ICAM-2 independent. A potent antiviral humoral response was associated with accumulation of hyper-stimulated cDC2s in ICAM null MedLNs and higher numbers of virus-specific T follicular helper (Tfh) cells generated following lung infection. Mice selectively depleted of cDC ICAM-1 expression supported, however, normal CTL and Tfh differentiation following influenza infection, ruling out essential co-stimulatory functions of DC ICAM-1 in CD8 + and CD4 + T cell differentiation. Collectively our findings suggest that lung ICAMs are dispensable for innate leukocyte trafficking to influenza infected lungs, for the generation of peri-epithelial T RM CD8 + cells, and long term anti-viral cellular immunity. In lung draining LNs, although ICAMs promote lymphocyte homing, these key integrin ligands are not required for influenza-specific humoral immunity or generation of IFN-γ effector CD8 + T cells. In conclusion, our findings suggest unexpected compensatory mechanisms that orchestrate protective anti-influenza immunity in the absence of vascular and extravascular ICAMs.","journal":"Frontiers in Immunology","year":2023,"id":370765,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9532,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1130103,"name":"Ofer Regev","orcid":"0000-0002-9775-3126","position":1,"is_corresponding":false},{"id":1130104,"name":"Anita Sapoznikov","orcid":"0000-0002-2543-7837","position":2,"is_corresponding":false},{"id":1130105,"name":"Marina Kizner","orcid":"0000-0003-0766-4849","position":3,"is_corresponding":false},{"id":1120867,"name":"Hagit Achdout","orcid":"0000-0003-0664-8628","position":4,"is_corresponding":false},{"id":988260,"name":"Ekaterina Petrovich‐Kopitman","orcid":"0000-0002-6050-6404","position":5,"is_corresponding":false},{"id":988514,"name":"Jacob Elkahal","orcid":"0000-0003-0157-7162","position":6,"is_corresponding":false},{"id":237397,"name":"Yoseph Addadi","orcid":"0000-0001-9827-0436","position":7,"is_corresponding":false},{"id":266071,"name":"Fernanda V. S. Castanheira","orcid":"0000-0002-2024-7858","position":8,"is_corresponding":false},{"id":289716,"name":"Sara W. Feigelson","orcid":"0000-0002-2535-9197","position":9,"is_corresponding":false},{"id":262889,"name":"Paul Kubes","orcid":"0000-0002-2835-4244","position":10,"is_corresponding":false},{"id":648549,"name":"Noam Erez","orcid":"0000-0001-5241-8028","position":11,"is_corresponding":false},{"id":246116,"name":"Natalio Garbi","orcid":"0000-0003-4144-6917","position":12,"is_corresponding":false},{"id":8022,"name":"R. 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