Sub‐optimal CD4+ T‐cell activation triggers autonomous TGF‐β‐dependent conversion to Foxp3+ regulatory T cells

Classical in vitro Treg conversion assays, which rely on optimal T‐cell activation in the presence of exogenous TGF‐β, induce Foxp3 expression at a frequency far above that which is observed in vivo in Treg‐dependent models of oral or transplantation tolerance. We have found that suboptimal murine T...

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Bibliographic Details
Published in:European journal of immunology 2011-05, Vol.41 (5), p.1249-1255
Main Authors: Oliveira, Vanessa G., Caridade, Marta, Paiva, Ricardo S., Demengeot, Jocelyne, Graca, Luis
Format: Article
Language:English
Subjects:
Animals
Antibodies, Neutralizing
Anti‐CD4
CD3 Complex - immunology
CD4 Antigens - immunology
CD4-Positive T-Lymphocytes - immunology
CD4-Positive T-Lymphocytes - metabolism
Cell Differentiation
Flow Cytometry
Forkhead Transcription Factors - genetics
Forkhead Transcription Factors - metabolism
Foxp3
Immune Tolerance
Lymphocyte Activation
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Transgenic
Receptors, Antigen, T-Cell - immunology
Receptors, Antigen, T-Cell - metabolism
T-Lymphocytes, Regulatory - cytology
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - metabolism
TGF‐b
Transforming Growth Factor beta - immunology
Transforming Growth Factor beta - metabolism
Transplantation tolerance
Treg
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Summary:Classical in vitro Treg conversion assays, which rely on optimal T‐cell activation in the presence of exogenous TGF‐β, induce Foxp3 expression at a frequency far above that which is observed in vivo in Treg‐dependent models of oral or transplantation tolerance. We have found that suboptimal murine T‐cell activation in vitro results in induction of Foxp3 expression, in the absence of exogenous TGF‐β, at a frequency similar to that which we found in vivo upon anti‐CD4‐induced transplantation tolerance. We show that TCR triggering with either low‐dose anti‐CD3 or low‐dose agonist peptide, as well as down‐modulation of the TCR signal with non‐depleting anti‐CD4, promotes TGF‐β production by T cells, an event that precedes Foxp3 expression and is Foxp3 independent. These findings support the view that sub‐immunogenic regimens lead to dominant tolerance as a result of T‐cell intrinsic properties.
ISSN:0014-2980
1521-4141
DOI:10.1002/eji.201040896