ABSTRACT: 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⁺ 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⁻/⁻ mice, suggesting that CXCR3-mediated protection requires adaptive immune cells. Adoptive transfer of CD4⁺ T cells from wild type (WT), but not CXCR3⁻/⁻, mice conferred protection in RAG2⁻/⁻ 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.
