IFN-γ-producing CD4+ T cells promote experimental cerebral malaria by modulating CD8+ T cell accumulation within the...

Area of Science:

• Immunology
• Infectious Diseases
• Neuroscience

Background:

• Interferon-gamma (IFN-γ) is crucial for experimental cerebral malaria (ECM) development in Plasmodium berghei ANKA infected mice.
• The specific cell types and timing of IFN-γ production during infection remain unclear.
• It is unknown if a single cell's IFN-γ can independently cause cerebral pathology.

Purpose of the Study:

• To investigate the temporal and tissue-specific sources of IFN-γ during Plasmodium berghei ANKA infection.
• To determine if IFN-γ production by a single cell type can induce cerebral pathology.
• To elucidate the role of CD4+ T cells in mediating ECM through IFN-γ.

Main Methods:

• Utilized IFN-γ reporter mice to track IFN-γ production.
• Adoptive transfer of wild-type CD4+ T cells into IFN-γ knockout mice.
• Depletion of endogenous CD8+ T cells to assess their role.
• Measured CXCL9 and CXCL10 chemokine expression in the brain.

Main Results:

• NK cells were the primary early IFN-γ producers in the brain, followed by CD4+ and CD8+ T cells.
• IFN-γ-producing CD4+ T cells, but not innate cells or CD8+ T cells, induced ECM in resistant mice.
• Adoptively transferred CD4+ T cells accumulated in multiple organs and induced ECM via IFN-γ secretion.
• Depleting CD8+ T cells blocked CD4+ T cell-induced ECM.
• CD4+ T cell-derived IFN-γ drove CXCL9/CXCL10 expression in the brain, enhancing CD8+ T cell recruitment.

Conclusions:

• CD4+ T cells are the critical cellular source of IFN-γ that drives experimental cerebral malaria.
• IFN-γ production by CD4+ T cells is sufficient to induce ECM pathology.
• This study reveals a key pathway where CD4+ T cell IFN-γ promotes ECM by recruiting CD8+ T cells via chemokine induction.