CXCR3 ameliorates neutrophil-dependent disease severity in SARS-CoV-2 infection by regulating CD4+ T cell recruitment

DOI record: { "DOI": "10.3389/fimmu.2026.1823264", "ISSN": [ "1664-3224" ], "URL": "http://dx.doi.org/10.3389/fimmu.2026.1823264", "abstract": "<jats:p>\n Understanding the host immune response to SARS-CoV-2 infection is critical for developing effective immunotherapeutic interventions. Using bulk RNA sequencing of lung tissue from mock-infected and mouse-adapted SARS-CoV-2 strain MA-10-infected mice, we identified CXCL9, CXCL10, and CXCL11 as among the most upregulated transcripts. Notably, their shared receptor, CXCR3, was also upregulated, suggesting activation of the CXCL9/10/11-CXCR3 axis in the lungs. Using spectral flow cytometry, we observed that the increased recruitment of CXCR3\n <jats:sup>+</jats:sup>\n immune cells, particularly T cells, innate lymphoid cells (ILCs), and macrophages, correlated with milder disease outcome. Blocking CXCR3 signaling using monoclonal antibodies resulted in worsened disease, which was accompanied by reduced recruitment of T cells, ILCs, and macrophages, and a marked increase in neutrophil infiltration. Depletion of neutrophils using αLy6G antibodies in CXCR3-blocked mice alleviated disease severity, indicating that CXCR3 signaling mitigated neutrophil-driven pathology. CXCR3 blockade failed to exacerbate disease in RAG2\n <jats:sup>-/-</jats:sup>\n mice, suggesting that CXCR3-mediated protection requires adaptive immune cells. Adoptive transfer of CD4\n <jats:sup>+</jats:sup>\n T cells from wild type (WT), but not CXCR3\n <jats:sup>-/-</jats:sup>\n , mice conferred protection in RAG2\n <jats:sup>-/-</jats:sup>\n mice. Together, our findings establish a protective role for CXCR3-recruited T cells blocking neutrophil infiltration in the lung, highlighting the mechanistic importance of the CXCL9/10/11-CXCR3 axis in protecting the lung from SARS-CoV-2 infection.\n </jats:p>", "alternative-id": [ "10.3389/fimmu.2026.1823264" ], "article-number": "1823264", "author": [ { "affiliation": [ { "name": "Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia Health System", "place": [ "Charlottesville, VA, United States" ] }, { "name": "Henry M Jackson Foundation for the Advancement of Military Medicine", "place": [ "Bethesda, VA, United States" ] } ], "family": "Uddin", "given": "Md Jashim", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "first" }, { "affiliation": [ { "name": "Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia Health System", "place": [ "Charlottesville, VA, United States" ] }, { "name": "Department of Microbiology, Immunology and Cancer Biology, School of Medicine, University of Virginia", "place": [ "Charlottesville, VA, United States" ] } ], "family": "Fleming", "given": "Claire", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia Health System", "place": [ "Charlottesville, VA, United States" ] }, { "name": "Neuroscience Graduate Program, University of Virginia", "place": [ "Charlottesville, VA, United States" ] } ], "family": "Natale", "given": "Nick R.", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia Health System", "place": [ "Charlottesville, VA, United States" ] }, { "name": "Department of Microbiology, Immunology and Cancer Biology, School of Medicine, University of Virginia", "place": [ "Charlottesville, VA, United States" ] } ], "family": "Hart", "given": "Duncan", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia Health System", "place": [ "Charlottesville, VA, United States" ] } ], "family": "Moreau", "given": "Brett", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Lydia Becker Institute of Immunology and Inflammation, School of Biological Sciences, University of Manchester, Manchester Academic Health Sciences Centre", "place": [ "Manchester, United Kingdom" ] }, { "name": "Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre", "place": [ "Manchester, United Kingdom" ] } ], "family": "Day", "given": "Anthony", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Lydia Becker Institute of Immunology and Inflammation, School of Biological Sciences, University of Manchester, Manchester Academic Health Sciences Centre", "place": [ "Manchester, United Kingdom" ] }, { "name": "Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre", "place": [ "Manchester, United Kingdom" ] } ], "family": "Allen", "given": "Judith", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia Health System", "place": [ "Charlottesville, VA, United States" ] }, { "name": "Department of Microbiology, Immunology and Cancer Biology, School of Medicine, University of Virginia", "place": [ "Charlottesville, VA, United States" ] }, { "name": "Neuroscience Graduate Program, University of Virginia", "place": [ "Charlottesville, VA, United States" ] }, { "name": "Department of Pathology, University of Virginia School of Medicine", "place": [ "Charlottesville, VA, United States" ] } ], "family": "Petri", "given": "William A.", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional", "suffix": "Jr." } ], "container-title": "Frontiers in Immunology", "container-title-short": "Front. Immunol.", "content-domain": { "crossmark-restriction": true, "domain": [ "frontiersin.org" ] }, "created": { "date-parts": [ [ 2026, 6, 11 ] ], "date-time": "2026-06-11T05:46:52Z", "timestamp": 1781156812000 }, "deposited": { "date-parts": [ [ 2026, 6, 11 ] ], "date-time": "2026-06-11T05:46:53Z", "timestamp": 1781156813000 }, "indexed": { "date-parts": [ [ 2026, 6, 11 ] ], "date-time": "2026-06-11T06:01:10Z", "timestamp": 1781157670141, "version": "3.54.1" }, "is-referenced-by-count": 0, "issued": { "date-parts": [ [ 2026, 6, 11 ] ] }, "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2026, 6, 11 ] ], "date-time": "2026-06-11T00:00:00Z", "timestamp": 1781136000000 } } ], "link": [ { "URL": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1823264/full", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "1965", 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