γδ-T cells promote IFN-γ-dependent Plasmodium pathogenesis upon liver-stage infection

Area of Science:

• Immunology
• Infectious Diseases
• Parasitology

Background:

• Cerebral malaria (CM) is a severe complication of Plasmodium infection, leading to significant mortality.
• The exact host and parasite factors driving CM pathogenesis are not fully understood.
• The role of gamma delta T cells (γδ-T cells) in experimental cerebral malaria (ECM) has been unclear.

Purpose of the Study:

• To investigate the role of γδ-T cells in the development of experimental cerebral malaria (ECM).
• To elucidate the mechanisms by which γδ-T cells influence Plasmodium infection and host immune responses in the context of ECM.

Main Methods:

• Infection of mice lacking γδ-T cells with Plasmodium berghei ANKA sporozoites (liver-infective stage) versus infected red blood cells (bypassing liver stage).
• Assessment of ECM susceptibility and severity in γδ-T cell deficient mice compared to wild-type controls.
• Analysis of Plasmodium immunogenic factor expression and inflammatory αβ-T cell responses.
• Evaluation of the role of Interferon-gamma (IFN-γ) in γδ-T cell-mediated pathology.

Main Results:

• Mice lacking γδ-T cells were resistant to ECM when infected via the natural liver-infective sporozoite route.
• Absence of γδ-T cells conferred susceptibility when mice were infected with red blood cells bypassing the liver stage.
• γδ-T cells promoted Plasmodium immunogenic factor expression and amplified systemic and brain-infiltrating inflammatory αβ-T cell responses.
• IFN-γ was essential for γδ-T cell-mediated modulation of parasite gene expression during the liver stage and subsequent immune pathology.

Conclusions:

• γδ-T cells play a critical, previously unrecognized role in the pathogenesis of experimental cerebral malaria following Plasmodium liver-stage infection.
• γδ-T cells exacerbate ECM by enhancing parasite immunogenicity and promoting inflammatory T cell responses, dependent on IFN-γ.