CD28 signaling via VAV/SLP-76 adaptors: regulation of cytokine transcription independent of TCR ligation

Immunity. 2001 Dec;15(6):921-33. doi: 10.1016/s1074-7613(01)00248-5.

Abstract

Since CD28 provides cosignals in T cell responses, a key question is whether the coreceptor operates exclusively via TCRzeta/CD3 or also operates as an independent signaling unit. In this study, we show that CD28 can cooperate with VAV/SLP-76 adaptors to upregulate interleukin 2/4 transcription independently of TCR ligation. CD28 signaling is dependent on VAV/SLP-76 complex formation and induces membrane localization of these complexes. CD28-VAV/SLP-76 also functions in nonlymphoid cells to promote nuclear entry of NFAT, indicating that these adaptors are the only lymphoid components needed for this pathway. Further downstream, CD28-VAV/SLP-76 synergizes with Rac1 and causes F-actin remodelling proximal to receptor. Autonomous CD28 signaling may account for the distinct nature of the second signal and in trans amplification of T cell responses.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / metabolism
  • Adaptor Proteins, Signal Transducing
  • Amino Acid Motifs
  • Animals
  • B7-1 Antigen / genetics
  • B7-1 Antigen / immunology
  • Biopolymers
  • CD28 Antigens / physiology*
  • CHO Cells
  • COS Cells
  • Cell Cycle Proteins*
  • Cell Membrane / metabolism
  • Chlorocebus aethiops
  • Cricetinae
  • Cricetulus
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation / physiology*
  • Humans
  • Interleukin-2 / biosynthesis*
  • Interleukin-2 / genetics
  • Interleukin-4 / biosynthesis*
  • Interleukin-4 / genetics
  • Jurkat Cells / immunology
  • Ligands
  • Lymphocyte Activation / physiology*
  • Macromolecular Substances
  • NFATC Transcription Factors
  • Nuclear Proteins*
  • Phosphoproteins / chemistry
  • Phosphoproteins / physiology*
  • Protein Binding
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-vav
  • Receptors, Antigen, T-Cell / immunology*
  • Recombinant Fusion Proteins / physiology
  • Signal Transduction / physiology*
  • T-Lymphocytes / immunology*
  • Transcription Factors / metabolism
  • Transcription, Genetic / physiology*
  • rac1 GTP-Binding Protein / physiology

Substances

  • Actins
  • Adaptor Proteins, Signal Transducing
  • B7-1 Antigen
  • Biopolymers
  • CD28 Antigens
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Interleukin-2
  • Ligands
  • Macromolecular Substances
  • NFATC Transcription Factors
  • Nuclear Proteins
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-vav
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • SLP-76 signal Transducing adaptor proteins
  • Transcription Factors
  • VAV1 protein, human
  • Interleukin-4
  • rac1 GTP-Binding Protein