The GARP/Latent TGF‐β1 complex on Treg cells modulates the induction of peripherally derived Treg cells during oral tolerance

Treg cells can secrete latent TGF‐β1 (LTGF‐β1), but can also utilize an alternative pathway for transport and expression of LTGF‐β1 on the cell surface in which LTGF‐β1 is coupled to a distinct LTGF‐β binding protein termed glycoprotein A repetitions predominant (GARP)/LRRC32. The function of the GA...

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Bibliographic Details
Published in:European journal of immunology 2016-06, Vol.46 (6), p.1480-1489
Main Authors: Edwards, Justin P., Hand, Timothy W., Morais da Fonseca, Denise, Glass, Deborah D., Belkaid, Yasmine, Shevach, Ethan M.
Format: Article
Language:English
Subjects:
Animals
Antigens - immunology
Biomarkers
Dendritic Cells - immunology
Dendritic Cells - metabolism
Forkhead Transcription Factors - metabolism
Foxp3
GARP
Gastrointestinal Microbiome - immunology
Gene Expression
Hypersensitivity, Delayed - genetics
Hypersensitivity, Delayed - immunology
Hypersensitivity, Delayed - metabolism
Immune Tolerance - genetics
Immunomodulation
Immunophenotyping
Integrins - genetics
Integrins - metabolism
Interleukin-2 - metabolism
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mice
Mice, Knockout
Phenotype
Protein Binding
T-Lymphocyte Subsets - immunology
T-Lymphocyte Subsets - metabolism
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - metabolism
TGF‐β
Tolerance
Transforming Growth Factor beta1 - metabolism
Treg cell
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Summary:Treg cells can secrete latent TGF‐β1 (LTGF‐β1), but can also utilize an alternative pathway for transport and expression of LTGF‐β1 on the cell surface in which LTGF‐β1 is coupled to a distinct LTGF‐β binding protein termed glycoprotein A repetitions predominant (GARP)/LRRC32. The function of the GARP/LTGF‐β1 complex has remained elusive. Here, we examine in vivo the roles of GARP and TGF‐β1 in the induction of oral tolerance. When Foxp3− OT‐II T cells were transferred to wild‐type recipient mice followed by OVA feeding, the conversion of Foxp3− to Foxp3+ OT‐II cells was dependent on recipient Treg cells. Neutralization of IL‐2 in the recipient mice also abrogated this conversion. The GARP/LTGF‐β1 complex on recipient Treg cells, but not dendritic cell‐derived TGF‐β1, was required for efficient induction of Foxp3+ T cells and for the suppression of delayed hypersensitivity. Expression of the integrin αvβ8 by Treg cells (or T cells) in the recipients was dispensable for induction of Foxp3 expression. Transient depletion of the bacterial flora enhanced the development of oral tolerance by expanding Treg cells with enhanced expression of the GARP/LTGF‐β1 complex. The major source of TGFβ1 required for the induction of antigen‐specific pTreg cells in vivo during oral tolerance is the activated Foxp3+ Treg cell. Active TGFβ1 is derived from the complex of GARP and latent‐TGFβ1 on the surface of Treg cells by the action of the integrin αvβ8.
ISSN:0014-2980
1521-4141
DOI:10.1002/eji.201546204