Cyclic AMP-mediated immune regulation--overview of mechanisms of action in T cells

Cell Signal. 2011 Jun;23(6):1009-16. doi: 10.1016/j.cellsig.2010.11.018. Epub 2010 Dec 2.


The canonical second messenger cAMP is well established as a potent negative regulator of T cell immune function. Through protein kinase A (PKA) it regulates T cell function at the level of transcription factors, members of the mitogen-activated protein kinase pathway, phospholipases (PLs), Ras homolog (Rho)A and proteins involved in the control of cell cycle progression. Type I PKA is the predominant PKA isoform in T cells. Furthermore, whereas type II PKA is located at the centrosome, type I PKA is anchored close to the T cell receptor (TCR) in lipid rafts by the Ezrin-ERM-binding phosphoprotein of 50 kDa (EBP50)-phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG) scaffold complex. The most TCR-proximal target for type I PKA is C-terminal Src kinase (Csk), which upon activation by raft recruitment and phosphorylation inhibits the Src family tyrosine kinases Lck and Fyn and thus functions to maintain T cell homeostasis. Recently, induction of cAMP levels in responder T cells has emerged as one of the mechanisms by which regulatory T (T(R)) cells execute their suppressive action. Thus, the cAMP-type I PKA-Csk pathway emerges as a putative target for therapeutic intervention in autoimmune disorders as well as in cancer, where T(R) cell-mediated suppression contributes to suboptimal local immune responses.

Publication types

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

MeSH terms

  • A Kinase Anchor Proteins / metabolism
  • Adenylyl Cyclases / metabolism
  • Animals
  • Cyclic AMP / immunology*
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Humans
  • Immunity, Cellular
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lymphocyte Activation
  • Membrane Microdomains
  • Protein Conformation
  • Signal Transduction
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • src-Family Kinases / metabolism


  • A Kinase Anchor Proteins
  • Intracellular Signaling Peptides and Proteins
  • Cyclic AMP
  • src-Family Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • Adenylyl Cyclases