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Mrp1 is involved in lipid presentation and iNKT cell activation by Streptococcus pneumoniae

Shilpi Chandra1, James Gray2, William B Kiosses1

  • 1Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92037, USA.

Nature Communications
|October 17, 2018
PubMed

Insights

Invariant natural killer T cells (iNKT cells) require CD1d presentation of lipid antigens. A genome screen identified HOPS, ESCRT, and ABC transporters, including Mrp1, crucial for this pathway and iNKT cell activation.

Area of Science:

  • Immunology
  • Cell Biology

Background:

  • Invariant natural killer T cells (iNKT cells) are crucial immune cells activated by lipid antigens presented by CD1d molecules.
  • The precise cellular mechanisms governing CD1d-mediated lipid antigen presentation are not fully understood.

Purpose of the Study:

  • To elucidate the cellular pathway involved in CD1d-mediated lipid antigen presentation using a whole-genome siRNA screen.
  • To investigate the role of specific genes and proteins, including the multidrug resistance protein 1 (Mrp1), in this process.

Main Methods:

  • A whole-genome siRNA screen was employed to identify genes affecting CD1d-mediated antigen presentation.
  • Knockdown effects on glycolipid-CD1d complex formation and iNKT cell activation were assessed.
  • In vivo studies utilized Mrp1 knockout mice infected with Streptococcus pneumoniae.

Main Results:

  • Gene knockdowns affecting HOPS, ESCRT complexes, cytoskeletal rearrangement, and ABC transporters reduced cell surface glycolipid-CD1d complex formation.
  • Mrp1 deficiency in vivo impaired CD1d clustering, leading to reduced iNKT cell activation.
  • Mrp1 knockout mice exhibited diminished iNKT cell responses to Streptococcus pneumoniae antigens and increased mortality.

Conclusions:

  • The study reveals key cellular components, including HOPS, ESCRT, and ABC transporters like Mrp1, essential for CD1d-mediated lipid antigen presentation.
  • The multidrug resistance protein 1 (Mrp1) plays a significant role in iNKT cell activation and host defense against bacterial infections.
  • Disruption of the lipid antigen presentation pathway can compromise immune responses and lead to severe outcomes.

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