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Cori Fain, PhD Candidate

The Abstract

Novel Role of MHC Class I in Cerebral Malaria

Ag-dependent Engagement of CD8+ T cells with H-2Kb on Brain Endothelium Required for CD8 Entry and Cerebral Manifestation of Malaria

Cori E Fain1,2 ,Jiaying Zheng1,3, Fang Jin1, Kathy Ayasoufi1, Zachariah P Tritz1,2, Roman Khadka1,2, Michael J Hansen2, Aaron J Johnson1,2

1Mayo Clinic Graduate School of Biomedical Sciences, Immunology, Rochester, MN, 2Mayo Clinic , Immunology, Rochester, MN, 3Mayo Clinic Graduate School of Biomedical Sciences, Neuroscience, Rochester, MN

Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection with high mortality. The immune system is a key participant as the cerebral manifestation is heavily reliant on CD8+ T cell infiltration and neuroinflammation. In this disease etiology, elevated blood cytokine levels lead to increased adhesion and antigen (Ag)-presenting molecules on brain endothelium prior to CD8+ T cell entry and onset of neurological symptoms. Using the animal model of experimental cerebral malaria (ECM) we sought to further define these interactions in vivo at the blood-brain barrier. While direct interaction with MHC class I on cerebrovascular endothelial cells (CECs) has been put forward as a putative mechanism for ECM, it has not been directly confirmed in vivo. We therefore hypothesized that Ag presentation by discrete MHC class I molecules on CECs would be required for CD8+ T cells to enter the brain and establish ECM. To test this, we crossed CDH5-Cre mice with novel H-2Kb LoxP and H-2Db LoxP mice to create endothelium-specific, individual class I cKO mice. In CDH5-Cre H-2Kb mice, we show that with T cell development fully intact; CD8+ T cell infiltration into the brain is decreased in frequency and number, both at baseline and during infection. T cells that do enter are increasingly naive with effector responses attenuated. Importantly, mice with loss of H-2Kb on CECs show extended survival and protection from cerebral complications; as assessed by 2-photon imaging, small-animal MRI and immunofluorescence. Together, these data demonstrate that parasite-specific CD8+ T cells must undergo Ag-dependent engagement with H-2Kb class I molecule on CECs in order to become the fully activated CD8+ T cells capable of entry to brain parenchyma; thus, mediating ECM development.

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