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Regulatory T cell main

Regulatory T cells are a heterogeneous subset of CD4+ T cells with suppressive properties that play a central role in maintaining CD4+ and CD8+ effector T cells, natural killer cells, NKT cells, and antigen-presenting cells through multiple mechanisms including the secretion of  immunosuppressive cytokines (IL-10, IL-35, and TGF-b) and metabolites (Adenosine), production of cytolytic factors (Granzymes A/B and Perforin), disruption of cell metabolism (i.e. IL-2 deprivation), and suppression of effector functions through direct cell-cell contact.

Several subsets of regulatory T cells exist. These include naturally occurring CD4+CD25+FoxP3+ cells that develop in the thymus, peripherally-derived regulatory T cells that are generated from FoxP3- conventional T cells at sites outside of the thymus, and induced regulatory T cells that are generated in vitro by stimulation of mouse conventional T cells with TGF-b.

Cells in the peripheral group have been further classified as either central regulatory T cells, effector regulatory T cells, or tissue-resident regulatory T cells. Additionally, CD4+FoxP3− type I regulatory T cells (Tr1), CD8+ regulatory T cells, and follicular regulatory T cells (TFR) have been described. Characteristics that distinguish these subsets as well as differences in their development and functional activity are active areas of investigation.

Mechanisms of Regulatory T Cell mediated suppression

Blood vessels graphic

There are several mechanisms by which regulatory T cells control the activity of other immune cells types. These include:

  • Secretion of TGF, IL-10, IL-35 and Galectin-1
    • Inhibits the differentiation, proliferation and activation of effector T cells
    • Suppresses cytokine production by effector T cells
    • IL-35 and TGF-b1 induce IL-10 production and regulate FoxP3 expression, promoting the maintenance and expansion of CD4+CD25+ Regulatory T  cells
  • Membrane-associated LAP-TGF-b1 (Latent TGF-b1)
    • Cell surface LAP-TGF-b1 (latent TGF-b1), complexed with LRRC32, suppresses the proliferation of activated Effector T  cells

  • High Levels of CD25/IL-2 Ra Expression
    • Depletes local IL-2, inhibiting activation and proliferation of effector T cells
    • IL-2 maintains CD4+CD25+ Regulatory T  cell populations
  • Generation of Extracellular Adenosine by Cell Surface Expression of CD39/CD73
    • Activation of A2A receptors by Adenosine blocks the expression of costimulatory molecules and growth factor receptors in Effector T  cells, inhibiting Effector T  cell activation, proliferation, and expansion

  • Transfer of Inhibitory cAMP through Gap Junctions
    • Inhibits Effector T  cell proliferation and IL-2 gene expression

  • Membrane-associated Galectin-1
    • Binds to GM1 ganglioside on Effector T cells
    • Induces cross-linking of associated integrins, triggering
    • TRPC5 channel activation and calcium influx, inhibiting
    • Effector T cell proliferation

  • Induction of Infectious Tolerance
    • In mice, membrane-associated LAP-TGF-b1 converts non-Regulatory T  cells into functional, FoxP3-expressing Regulatory T cells

  • Granzyme A/B Secretion
    • Granzyme A/B induces apoptosis in DCs and Effector T  cells in both a perforin-dependent and -independent manner

  • Binding of LAG-3 to MHC II
    • Induces an immunoreceptor tyrosine-based activation motif (ITAM)-mediated inhibitory signaling pathway, blocking the maturation and immunostimulatory capacity of DCs

  • CTLA-4-dependent Suppression
    • CTLA-4 interacts with B7 (CD80 and CD86) on DCs, triggering indoleamine 2, 3- dioxygenase (IDO) expression (which is also induced by IFN-g receptor stimulation)
    • IDO catabolizes tryptophan, depleting stores needed for Effector T  cell proliferation, and producing the pro-apoptotic metabolite Ν-formylkynurenine

Regulatory T Cell Resources

Cell Resource

Click on the images below to find out more about other immune cell types.

Macrophage cellNeutrophil cellRegulatory T CellCytotoxic T CellNatural killer CellDendritic cell