T cell-specific P2RX7 favors lung parenchymal CD4⁺ T cell accumulation in response to severe lung infections

CD4⁺ T cells are key components of the immune response during lung infections and can mediate protection against tuberculosis (TB) or influenza. However, CD4⁺ T cells can also promote lung pathology during these infections, making it unclear how these cells control such discrepant effects. Using mouse models of hypervirulent TB and influenza, we observe that exaggerated accumulation of parenchymal CD4⁺ T cells promotes lung damage. Low numbers of lung CD4⁺ T cells, in contrast, are sufficient to protect against hypervirulent TB. In both situations, lung CD4⁺ T cell accumulation is mediated by CD4⁺ T cell-specific expression of the extracellular ATP (eATP) receptor P2RX7. P2RX7 upregulation in lung CD4⁺ T cells promotes expression of the chemokine receptor CXCR3, favoring parenchymal CD4⁺ T cell accumulation. Our findings suggest that direct sensing of lung eATP by CD4⁺ T cells is critical to induce tissue CD4⁺ T cell accumulation and pathology during lung infections.