J Immunol. 2026 Mar 17;215(3):vkag017. doi: 10.1093/jimmun/vkag017.
ABSTRACT
Chemokines play a crucial role in the lung’s immune responses to infections and diseases. The role of CXC ligand 13 (CXCL13), a chemokine produced homeostatically by various lung cell types, in protecting against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and disease remains controversial. Some studies reported that patients who survived severe coronavirus disease 2019 (COVID-19) had CXCL13-dominated lung immune responses early in infection. In contrast, other studies reported that high CXCL13 levels were associated with severe COVID-19. In this study, to determine the direct role of CXCL13 in SARS-CoV-2 infection and disease, we generated CXCL13-/-K18-hACE2 mice, that are both transgenic for ACE2 and deficient in CXCL13, and compared their infection and COVID-19-like symptoms with those in wild-type K18-hACE2 transgenic mouse littermates following intranasal inoculation with the pathogenic SARS-CoV-2 delta variant (B.1.617.2). Compared to age- and gender-matched SARS-CoV-2 infected wild-type K18-hACE2 mice, the SARS-CoV-2 infected CXCL13-/-K18-hACE2 deficient mice exhibited (i) higher viral load in the lungs; (ii) severe COVID-19-like lung pathology; (iii) exacerbated weight loss; and (iv) increased mortality. The apparent severe COVID-19-like symptoms in CXCL13-/-K18-hACE2 deficient mice were associated with: (i) significantly lower frequencies of functional lung-resident C-X-C chemokine receptor 5+ (CXCR5)+CD19+ B-cells, follicular CXCR5+CD4+ helper T cells (Tfh cells), and effector IFN-γ+TNF-α+GzmB+Ki67+ CD4+ Th1 cells; and (ii) a significant reduction in the levels of SARS-CoV-2-Spike specific IgG1 and IgG2b antibody isotypes. These findings corroborate previous human reports suggesting a protective role for the CXCL13/CXCR5 chemokine axis in combating SARS-CoV-2 infection and disease by promoting B cell- and T cell-mediated immunity, offering a potential new immunotherapeutic target.
PMID:41847859 | DOI:10.1093/jimmun/vkag017