The role of tyrosine phosphorylation and PTP-1C in CTLA-4 signal transduction

Eur J Immunol. 1996 Dec;26(12):3224-9. doi: 10.1002/eji.1830261257.


Recently, there has been increasing interest in the inhibitory regulators of lymphocyte activation, and in particular, the role of CD28 homologue CTLA-4 in the regulation of T cell responses. Interaction of CTLA-4 with B7 ligands inhibits T cell responses, including T cell proliferation and interleukin-2 (IL-2) secretion. The mechanism(s) responsible for CTLA-4 signal transduction are unknown, but it has been suggested that tyrosine phosphorylation is involved. Here we demonstrate that phorbol ester phorbol 12-myrislate 13-acetate (PMA), which increases tyrosine phosphorylation by stimulating protein kinase C and p21ras, can overcome the CTLA-4-mediated inhibition of T cell proliferation. This provides the first functional evidence that tyrosine phosphorylation is involved in CTLA-4 signal transduction. Most interestingly, CTLA-4-mediated inhibition of IL-2 secretion was not influenced by the presence of PMA. Further, we demonstrate that CTLA-4 cross-linking inhibits proliferation and IL-2 secretion of T cells from motheaten mice. These mice lack PTP-1C, a tyrosine phosphatase which mediates in a number of lymphocyte inhibitory responses, indicating that PTP-1C is not essential for CTLA-4 signaling. Collectively, these results demonstrate that regulation of tyrosine phosphorylation plays a pivotal role in CTLA-4 function, and that the inhibition of the transition from G0/G1 to the S phase of the cell cycle and the inhibition of IL-2 secretion require distinct signaling pathways. These experiments provide a useful model system which can be used to elucidate the signaling pathways involved in CTLA-4 function and to understand how CTLA-4, CD28 and Tcell receptor-mediated signals are integrated in T cell responses to antigen.

Publication types

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

MeSH terms

  • Abatacept
  • Animals
  • Antigens, CD
  • Antigens, Differentiation / pharmacology*
  • CTLA-4 Antigen
  • Immunoconjugates*
  • Interleukin-2 / pharmacology
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation / drug effects
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases / analysis*
  • Protein Tyrosine Phosphatases / pharmacology
  • Protein-Tyrosine Kinases / analysis*
  • Protein-Tyrosine Kinases / pharmacology
  • Signal Transduction / drug effects*


  • Antigens, CD
  • Antigens, Differentiation
  • CTLA-4 Antigen
  • Ctla4 protein, mouse
  • Immunoconjugates
  • Interleukin-2
  • Intracellular Signaling Peptides and Proteins
  • Abatacept
  • Protein-Tyrosine Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • Ptpn11 protein, mouse
  • Ptpn6 protein, mouse