The lymphoid lineage-specific actin-uncapping protein Rltpr is essential for costimulation via CD28 and the development of regulatory T cells

Nat Immunol. 2013 Aug;14(8):858-66. doi: 10.1038/ni.2634. Epub 2013 Jun 23.

Abstract

Although T cell activation can result from signaling via T cell antigen receptor (TCR) alone, physiological T cell responses require costimulation via the coreceptor CD28. Through the use of an N-ethyl-N-nitrosourea-mutagenesis screen, we identified a mutation in Rltpr. We found that Rltpr was a lymphoid cell-specific, actin-uncapping protein essential for costimulation via CD28 and the development of regulatory T cells. Engagement of TCR-CD28 at the immunological synapse resulted in the colocalization of CD28 with both wild-type and mutant Rltpr proteins. However, the connection between CD28 and protein kinase C-θ and Carma1, two key effectors of CD28 costimulation, was abrogated in T cells expressing mutant Rltpr, and CD28 costimulation did not occur in those cells. Our findings provide a more complete model of CD28 costimulation in which Rltpr has a key role.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • CARD Signaling Adaptor Proteins / immunology*
  • CD28 Antigens / immunology*
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Flow Cytometry
  • Guanylate Cyclase / immunology*
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microfilament Proteins
  • Microscopy, Confocal
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Protein Kinase C / immunology*
  • Receptors, Antigen, T-Cell / immunology*
  • Sequence Alignment
  • Sequence Analysis, DNA
  • Specific Pathogen-Free Organisms
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • CARD Signaling Adaptor Proteins
  • CD28 Antigens
  • Carrier Proteins
  • LRRC16A protein, human
  • Microfilament Proteins
  • Receptors, Antigen, T-Cell
  • Protein Kinase C
  • CARD11 protein, human
  • Guanylate Cyclase