Protein Tyrosine Phosphatase Inhibition Prevents Experimental Cerebral Malaria by Precluding CXCR3 Expression on T Cells

Kristin M Van Den Ham,Martin Olivier,Martin J Richer,Logan K Smith

doi:10.1038/s41598-017-05609-1

Kristin M Van Den Ham, Martin Olivier + Show 2 more

Open Access

https://doi.org/10.1038/s41598-017-05609-1

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Abstract

Cerebral malaria induced by Plasmodium berghei ANKA infection is dependent on the sequestration of cytotoxic T cells within the brain and augmentation of the inflammatory response. Herein, we demonstrate that inhibition of protein tyrosine phosphatase (PTP) activity significantly attenuates T cell sequestration within the brain and prevents the development of neuropathology. Mechanistically, the initial upregulation of CXCR3 on splenic T cells upon T cell receptor stimulation was critically decreased through the reduction of T cell-intrinsic PTP activity. Furthermore, PTP inhibition markedly increased IL-10 production by splenic CD4+ T cells by enhancing the frequency of LAG3+CD49b+ type 1 regulatory cells. Overall, these findings demonstrate that modulation of PTP activity could possibly be utilized in the treatment of cerebral malaria and other CXCR3-mediated diseases.

Highlights

The role of inflammation in ECM is poorly defined
To determine the impact of reduced tyrosine phosphatase activity on the pathology of ECM, mice were treated with the protein tyrosine phosphatase (PTP) inhibitor, bpV(phen), daily from 3 days before to 12 days after infection with P. berghei ANKA. bpV(phen) targets a conserved catalytic cysteine, resulting in a general inhibition of PTP activity[29, 30]
We demonstrate that bpV(phen) treatment throughout the infection precludes the development of cerebral and hepatic pathology during P. berghei ANKA infection and rescues infected animals from ECM-induced mortality

Summary

Introduction

The role of inflammation in ECM is poorly defined. IL-10 is an important immune regulator that can suppress inflammation[13]. IL-10 production by Foxp3− regulatory CD4+ T cells has been shown to mitigate pathology in non-cerebral murine malaria[15, 16]. Signal transduction downstream of TCR stimulation relies on a dynamic tyrosine phosphorylation cascade, regulated by the opposing activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs)[20]. Shown to cause at least partial T cell activation[21, 22], but the impact of PTP inhibition in conjunction with TCR stimulation is unknown. The underlying pathological mechanisms that are modulated by tyrosine phosphorylation are largely undefined, we were interested in examining the impact of direct PTP inhibition on the T cell response and on the regulation of infection-induced inflammation during ECM

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