Interleukin-2 receptor downstream events in regulatory T cells: implications for the choice of immunosuppressive drug therapy - PubMed (original) (raw)

Review

. 2008 Feb 15;7(4):458-62.

doi: 10.4161/cc.7.4.5454. Epub 2007 Dec 18.

Affiliations

Review

Interleukin-2 receptor downstream events in regulatory T cells: implications for the choice of immunosuppressive drug therapy

Robert Zeiser et al. Cell Cycle. 2008.

Abstract

Naturally occurring CD4+CD25(high)FOXP3+ regulatory T cells (Tregs) constitute a powerful mechanism of immune regulation and therefore, have important therapeutic potential for disorders such as autoimmune diseases, allograft rejection and graft-versus-host disease. Disruption of the IL-2R signalling pathway by genetic defects of the interleukin (IL)-2 gene or components of the IL-2 receptor (R) complex results in severe T cell-mediated autoimmunity rather than immunodeficiency, indicating a crucial role for IL-2R signalling for Treg development and function. Signalling downstream of the IL-2R can act through the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway, the Janus kinase (JAK)/Signal transducers and Activators of Transcription (STAT) pathway and the mitogen-activated protein kinase (MAPK) pathway. In this report we focus on the relevance of these pathways as well as the impact of immunosuppressive drugs that may affect or enhance Treg function by targeting IL-2R signalling.

PubMed Disclaimer

Figures

Figure 1

Figure 1

Signalling through growth factor receptors can activate the PI3K/Akt/mTOR pathway and the JAK3/STAT5 pathway. (A) Growth factor receptors first stimulate PI 3 kinase, and through inositol phosphates activate AKT which then phosphorylates mTOR. The phosphorylation of p70S6K and 4EBP by mTOR and the phosphorylation downstream of RPS6 and EIF-4B stimulate translational initiation and contribute to cell growth. The activity of the mTOR pathway is controlled by PTEN a phosphoinositol 3,4,5-triphosphatase that catalyzes the reverse reaction of PI3K. Rapamycin (RAPA) inhibits mTOR kinase activity and has immunosuppressant activity on cells that use the mTOR pathway in the absence of PTEN inhibition. (B) Engagement of Growth factor receptors leads to activation of JAK3 which induces phospharylation and nuclear translocation of STAT5. The Foxp3 promotor has several STAT5B consensus sequences that can be bound and lead to promotor activity. Abbreviations: PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; PTEN, phosphatase and tensin homolog deleted on chromosome 10; RAPA, rapamycin; mTOR, mammalian target of rapamycin; p, phosphorylation; JAK, Janus kinase; STAT, signal transducer and activator of transcription; Foxp3, forkhead box P3.

Similar articles

Cited by

References

    1. Stephens LA, Mottet C, Mason D, Powrie F. Human CD4(+)CD25(+) thymocytes and peripheral T cells have immune suppressive activity in vitro. Eur J Immunol. 2001;31:1247–54. - PubMed
    1. Nelson BH. IL-2, regulatory T cells, and tolerance. J Immunol. 2004;172:3983–8. - PubMed
    1. Furtado G, de Lafaille MAC, Kutchukhidze N, Lafaille JJ. Interleukin-2 signaling is required for CD4+ regulatory T-cell function. J Exp Med. 2002;196:851–7. - PMC - PubMed
    1. Thornton A, Donovan EE, Piccirillo CA, Shevach EM. Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function. J Immunol. 2004;172:6519–23. - PubMed
    1. Nelson BH, McIntosh BC, Rosencrans LL, Greenberg PD. Requirement for an initial signal from the membrane-proximal region of the interleukin 2 receptor gamma(c) chain for Janus kinase activation leading to T cell proliferation. Proc Natl Acad Sci USA. 1997;94:1878–83. - PMC - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources