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Cyclic AMP-mediated immune regulation--overview of mechanisms of action in T cells
Randi Mosenden1, Kjetil Taskén
1The Biotechnology Centre of Oslo and Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, P.O. Box 1125 Blindern, N-0317 Oslo, Norway.
Abstract:
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.
Insights
The cyclic AMP (cAMP) pathway, specifically type I protein kinase A (PKA), inhibits T cell function by targeting C-terminal Src kinase (Csk). This pathway is crucial for T cell homeostasis and immune suppression by regulatory T cells.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Cyclic AMP (cAMP) is a key second messenger regulating T cell immune function.
- Protein kinase A (PKA) mediates cAMP's effects on transcription factors, signaling pathways, and cell cycle progression.
- Type I PKA is the primary isoform in T cells, localized near the T cell receptor (TCR) via a specific scaffold complex.
Purpose of the Study:
- To elucidate the molecular mechanisms of cAMP-mediated T cell regulation.
- To investigate the role of the type I PKA-Csk pathway in T cell homeostasis and immune suppression.
- To identify the cAMP-type I PKA-Csk pathway as a potential therapeutic target.
Main Methods:
- Analysis of PKA isoform localization and function in T cells.
- Investigating the interaction between PKA, TCR, and associated scaffold proteins.
- Studying the phosphorylation and activation of C-terminal Src kinase (Csk) by type I PKA.
- Examining the impact of cAMP induction on T cell function and regulatory T cell (Treg) activity.
Main Results:
- Type I PKA is anchored near the TCR in lipid rafts by the EBP50-PAG scaffold complex.
- Type I PKA directly phosphorylates and activates Csk, inhibiting Src family kinases (Lck, Fyn) and maintaining T cell homeostasis.
- Increased cAMP levels in T cells contribute to the suppressive function of regulatory T cells (Tregs).
Conclusions:
- The cAMP-type I PKA-Csk pathway is a critical regulator of T cell activation and immune homeostasis.
- This pathway is implicated in the suppressive mechanisms employed by regulatory T cells.
- Targeting the cAMP-type I PKA-Csk pathway offers a potential therapeutic strategy for autoimmune diseases and cancer.
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