Comprehensive immune profiling reveals IFN-γ signaling in T cells mediates parasite phagocytosis in a rodent malaria model

Pulmonary manifestation in malaria can be life-threatening. Using a rodent malaria model and comprehensive transcriptomics analyses to illustrate the immune landscape of malaria-associated lung pathology, we identified that IFN-γ signaling in T cells plays an important role in malaria-associated lung pathology. Disruption of IFN-γ signaling in T cells leads to reduced parasite load in the lungs and attenuated lung pathology by enhancing T cell-monocyte interaction. Surprisingly, the stronger interaction leads to an increase in a proinflammatory monocyte subset characterized by CD8 and Ly6C expression, which exhibits prominently elevated phagocytic capacity compared to the CD8^- counterpart. Our study illustrates the importance of IFN-γ signaling in T cell-monocyte interaction in malaria-associated lung pathology, highlighting the complex and intricate immune network induced by the <i>Plasmodium</i> infection.IMPORTANCEMalaria-associated lung pathology is a common complication of malaria in adults and often occurs during or even after antimalarial treatment, and current evidence suggests that it is associated with cytokine imbalance and dysregulation of immune responses in the lungs. In this study, we conducted detailed flow cytometry analyses, time-series bulk transcriptomics, and spatial transcriptomics to profile the immune landscape of malaria-associated lung pathology in a mouse malaria model and revealed that IFN-γ signaling in T cells plays a key role in the lung pathology. In addition, we identified a subgroup of CD8-expressing proinflammatory monocytes that exhibit heightened parasite phagocytotic capability.