CTL lymph node entrapment drives lymphopenia in severe influenza infection

Influenza virus infection can result in outcomes ranging from moderate, self-limiting illness to severe, life-threatening disease. Although severe cases are frequently associated with CD8⁺ T cell lymphopenia, the underlying mechanisms driving this diminished T cell response remain poorly defined. Here, we investigated how severe influenza infection alters CD8⁺ T cell activation and trafficking. While CD8⁺ T cell priming was comparable between moderate and severe influenza infections, we found that during severe disease, effector CD8⁺ T cells were retained within the lung-draining lymph nodes (dLN). This entrapment was, in part, associated with a failure of effector CD8⁺ T cells to re-express the transcription factor KLF2 and its downstream target, the sphingosine-1-phosphate receptor S1PR₁, a defect we show to be independent of both TGFβ and sustained TCR signalling. To evaluate the consequences of this impaired trafficking, we transferred effector CD8⁺ T cells directly into the bloodstream during severe influenza infection and found that intravenously delivered cells were rapidly and selectively eliminated upon entry into the inflamed lung. Our findings reveal that CD8⁺ T cell lymphopenia observed during severe influenza infection arises from two key mechanisms: sequestration of effector CD8⁺ T cells within the dLN and selective elimination of antigen-specific effectors within the lung tissue.