Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells

@article{Wang2009ExpressionOG,
  title={Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells},
  author={Rui Wang and Lina Kozhaya and Frances Mercer and Alka Khaitan and Hodaka Fujii and Derya Unutmaz},
  journal={Proceedings of the National Academy of Sciences},
  year={2009},
  volume={106},
  pages={13439 - 13444}
}
The molecules that define human regulatory T cells (Tregs) phenotypically and functionally remain to be fully characterized. We recently showed that activated human Tregs express mRNA for a transmembrane protein called glycoprotein A repetitions predominant (GARP, or LRRC32). Here, using a GARP-specific mAb, we demonstrate that expression of GARP on activated Tregs correlates with their suppressive capacity. However, GARP was not induced on T cells activated in the presence of TGFβ, which… 

Figures from this paper

GARP–TGF-β Complexes Negatively Regulate Regulatory T Cell Development and Maintenance of Peripheral CD4+ T Cells In Vivo

A role for GARP is suggested in natural and induced Treg development through activation of bound latent TGF-β and signaling, which negatively regulates GARP expression on Tregs.

Helios, and not FoxP3, is the marker of activated Tregs expressing GARP/LAP

Therapeutic modalities for treating autoimmune and inflammatory diseases, allergies and graft rejection should be designed to induce and/or expand FoxP3+Helios+ Tregs, while therapies against cancers or infectious diseases should avoid such expansion/induction.

Helios Expression Is a Marker of T Cell Activation and Proliferation

Investigation of Helios expression in murine and human T cells under resting or activating conditions, using well-characterized molecules of naïve/effector/memory phenotypes, as well as a set of Treg-associated markers found that Helios-negative T cells are enriched for naïve T cell phenotypes and vice versa.

FOXP3 Expression in GARP-Transduced Helper T Cells Is Not Associated with FOXP3 TSDR Demethylation

Although GARP-engineered Th cells exhibit stable FOXP3 expression and a phenotypic reprogramming towards T Reg cells in vitro, these cells do not completely mimic the epigenotype of natural Treg cells and concepts based on the genetic modification of Th cells should be critically tested before any clinical application.

GARP Dampens Cancer Immunity by Sustaining Function and Accumulation of Regulatory T Cells in the Colon.

It is demonstrated that loss of GARP in Treg cells leads to spontaneous inflammation with highly activated CD4+ and CD8+ T cells and development of enteritis, highlighting the importance of cell surface TGFβ in T Reg function and GARP as a potential therapeutic target for colorectal cancer therapy.

The Tregs' world according to GARP

A study provides further demonstration that GARP is selectively expressed only in activated human nT Reg and nTreg cell clones but not in activated effector T cells, confirming GARP as a bona fide nTReg marker.

Impairment of Circulating CD4+CD25+GARP+ Regulatory T Cells in Patients with Acute Coronary Syndrome

It is indicated that circulating CD4+CD25+GARP+ Tregs are impaired in patients with acute coronary syndrome, and targeting GARP may promote the protective function of T Regs in ACS.

Human treg cells are characterized by low/negative CD6 expression

Evidence is presented that CD4+CD25hi CD6lo/− nTreg have high expression of FOXP3and exhibit in vitro suppressive activity on CD8+ T‐cell proliferation, providing a new tool for the identification of nT Reg cells without recourse to intracellular staining, and for the purification of these cells by negative selection.

Regulation of the Expression of GARP/Latent TGF-β1 Complexes on Mouse T Cells and Their Role in Regulatory T Cell and Th17 Differentiation

GARP-deficient Tregs develop normally, are present in normal numbers in peripheral tissues, and are fully competent suppressors of the activation of conventional T cells in vitro.
...

References

SHOWING 1-10 OF 28 REFERENCES

Identification of a Regulatory T Cell Specific Cell Surface Molecule that Mediates Suppressive Signals and Induces Foxp3 Expression

Findings reveal a novel cell surface molecule-mediated regulatory mechanism, called GARP, which within T cells is specifically expressed in Tregs activated through the T cell receptor (TCR), with implications for modulating aberrant immune responses.

Naive Precursors of Human Regulatory T Cells Require FoxP3 for Suppression and Are Susceptible to HIV Infection1

It is proposed that TNreg cells are precursors for human Treg cells and that these cells require a high level of FoxP3 expression to maintain their suppressive function, and modulation of TNreg cell numbers during infections such as HIV may disrupt human T Reg cell development, and contribute to chronic immune activation.

Generation of potent and stable human CD4+ T regulatory cells by activation-independent expression of FOXP3.

A lentivirus-based strategy to ectopically express high levels of FOXP3 that do not fluctuate with the state of T-cell activation consistently results in the development of suppressive cells that are as potent as Tregs and can be propagated as a homogeneous population.

Inducible reprogramming of human T cells into Treg cells by a conditionally active form of FOXP3

First formal evidence that FOXP3 acts as a quantitative regulator rather than a simple molecular switch for Treg is presented, providing evidence that secretion of IL‐35 does not substantially contribute to the suppressive mechanism of human Treg.

Identification of IL-17-producing FOXP3+ regulatory T cells in humans

It is reported that human peripheral blood and lymphoid tissue contain a significant number of CD4+FOXP3+ T cells that express CCR6 and have the capacity to produce IL-17 upon activation, and it is shown that human CD4-FO XP3+CCR6− regulatory T (Treg) cells differentiate into IL- 17 producer cells upon T-cell receptor stimulation.

CD4+FoxP3+ regulatory T cells confer infectious tolerance in a TGF-β–dependent manner

It appears that TR associated TGF‐β can play a role in suppression of activated effectors, but more importantly can mediate infectious tolerance by converting conventional T cells into TR.

HIV Infection of Naturally Occurring and Genetically Reprogrammed Human Regulatory T-cells

The ability to reprogram human T-cells into Treg cells in vitro will greatly aid in decoding their mechanism of suppression, their enhanced susceptibility to HIV infection, and the unique markers expressed by this subset.

Persistence of naive CD45RA+ regulatory T cells in adult life.

Sorted CD4+CD25+CD45RA+ T cells from both cord and adult blood expressed very high levels of mRNA for Foxp3 and manifested equivalent suppressive activity in vitro, indicating that they are bone fide members of the regulatory T-cell lineage.

Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells.

FoxP3 is a crucial regulatory gene for the development and function of CD25(+)CD4(+) regulatory T cells, and can be used as their reliable marker for treatment of autoimmune/inflammatory diseases and negative control of various immune responses.

In vivo expansion of CD4CD45RO-CD25 T cells expressing foxP3 in IL-2-treated HIV-infected patients.

In vivo IL-2 administration to HIV-infected patients leads to peripheral expansion of a population of long-lived CD4CD45ROCD25 cells that express high levels of foxP3 but exert weak suppressive function, which play a role in the maintenance of a state of low turnover and sustained expansion of the CD4 T cell pool.