tetano
Editor, Senior Moderator
Front Immunol
. 2026 Jun 11:17:1823264.
doi: 10.3389/fimmu.2026.1823264. eCollection 2026.
CXCR3 ameliorates neutrophil-dependent disease severity in SARS-CoV-2 infection by regulating CD4[SUP]+[/SUP] T cell recruitment
Md Jashim Uddin[SUP] 1 2 [/SUP], Claire Fleming[SUP] 1 3 [/SUP], Nick R Natale[SUP] 1 4 [/SUP], Duncan Hart[SUP] 1 3 [/SUP], Brett Moreau[SUP] 1 [/SUP], Anthony Day[SUP] 5 6 [/SUP], Judith Allen[SUP] 5 6 [/SUP], William A Petri Jr[SUP] 1 3 4 7 [/SUP]
Affiliations
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[SUP]+[/SUP] 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[SUP]-/-[/SUP] mice, suggesting that CXCR3-mediated protection requires adaptive immune cells. Adoptive transfer of CD4[SUP]+[/SUP] T cells from wild type (WT), but not CXCR3[SUP]-/-[/SUP], mice conferred protection in RAG2[SUP]-/-[/SUP] 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.
Keywords: CD4+T cells; COVID-19; CXCR3; SARS-CoV-2; neutrophils.
. 2026 Jun 11:17:1823264.
doi: 10.3389/fimmu.2026.1823264. eCollection 2026.
CXCR3 ameliorates neutrophil-dependent disease severity in SARS-CoV-2 infection by regulating CD4[SUP]+[/SUP] T cell recruitment
Md Jashim Uddin[SUP] 1 2 [/SUP], Claire Fleming[SUP] 1 3 [/SUP], Nick R Natale[SUP] 1 4 [/SUP], Duncan Hart[SUP] 1 3 [/SUP], Brett Moreau[SUP] 1 [/SUP], Anthony Day[SUP] 5 6 [/SUP], Judith Allen[SUP] 5 6 [/SUP], William A Petri Jr[SUP] 1 3 4 7 [/SUP]
Affiliations
- PMID: 42367761
- PMCID: PMC13294051
- DOI: 10.3389/fimmu.2026.1823264
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[SUP]+[/SUP] 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[SUP]-/-[/SUP] mice, suggesting that CXCR3-mediated protection requires adaptive immune cells. Adoptive transfer of CD4[SUP]+[/SUP] T cells from wild type (WT), but not CXCR3[SUP]-/-[/SUP], mice conferred protection in RAG2[SUP]-/-[/SUP] 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.
Keywords: CD4+T cells; COVID-19; CXCR3; SARS-CoV-2; neutrophils.