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PDL1 Fusion Protein Protects Against Experimental Cerebral Malaria via Repressing Over-Reactive CD8+ T Cell Responses

Jun Wang1,2, Yue Li1, Yan Shen1

  • 1Department of Medical Microbiology and Parasitology, Fourth Military Medical University, Xi'an, China.

Frontiers in Immunology
|January 30, 2019
PubMed

Insights

Programmed death-1 (PD-1) pathway modulation using PDL1-IgG1Fc protein offers a promising strategy to combat lethal cerebral malaria (CM). This treatment protects the brain by regulating CD8+ T cells and macrophages, improving survival in experimental models.

Area of Science:

  • Immunology
  • Neuroscience
  • Infectious Diseases

Background:

  • Cerebral malaria (CM), primarily caused by Plasmodium falciparum, is a life-threatening complication of severe malaria.
  • Pathogenesis of CM involves immunopathology driven by CD8+ T cells infiltrating the brain, necessitating novel therapeutic strategies.
  • The programmed death-1 (PD-1) pathway is a key regulator of immune responses and a potential therapeutic target.

Purpose of the Study:

  • To investigate the therapeutic potential of soluble fusion proteins, PDL1-IgG1Fc and PDL2-IgG1Fc, for treating CM.
  • To evaluate the role of the PD-1/PDL signaling pathway in CM pathogenesis and host protection.
  • To assess the impact of PDL1-IgG1Fc on immune cell function and blood-brain barrier integrity during experimental CM (ECM).

Main Methods:

  • Construction of soluble fusion proteins: PDL1-IgG1Fc and PDL2-IgG1Fc.
  • Utilized PD-1-deficient (Pdcd1-/-) and wild-type (WT) mice to study PD-1 pathway function.
  • Administered PDL1-IgG1Fc to mice during experimental cerebral malaria (ECM) and assessed survival, immune cell activity, and blood-brain barrier integrity.

Main Results:

  • PD-1 pathway deficiency resulted in increased CD8+ T cell proliferation and reduced survival in mice.
  • Treatment with PDL1-IgG1Fc significantly prolonged survival in mice with experimental CM (ECM).
  • PDL1-IgG1Fc ameliorated blood-brain barrier disruption by suppressing CD8+ T cell cytotoxicity and M1 polarization of macrophages.

Conclusions:

  • Enhancing PD-1/PDL signaling via PDL1-IgG1Fc administration is a promising strategy for protecting against CM.
  • Early-stage intervention with PDL1-IgG1Fc helps maintain immune homeostasis in the brain during ECM.
  • PDL1-IgG1Fc demonstrates potential as a future therapeutic candidate for cerebral malaria treatment.
Keywords:
CD8+ T cellPD-1/PDL1experimental cerebral malariaimmunotherapymacrophage

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