Cutting Edge: Tissue Antigen Expression Levels Fine-Tune T Cell Differentiation Decisions In Vivo

Immune homeostasis in peripheral tissues is, to a large degree, maintained by the differentiation and action of regulatory T cells (Treg) specific for tissue Ags. Using a novel mouse model, we have studied the differentiation of naive CD4 T cells into Foxp3 Treg in response to a cutaneous Ag (OVA)....

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Bibliographic Details
Published in:The Journal of immunology (1950) 2020-11, Vol.205 (10), p.2577-2582
Main Authors: Pinheiro, Douglas F, Szenes-Nagy, Antal B, Maurano, Megan M, Lietzenmayer, Melanie, Klicznik, Maria M, Holly, Raimund, Kirchmeier, Daniel, Kitzmueller, Sophie, Achatz-Straussberger, Gertrude, Rosenblum, Michael D, Thalhamer, Josef, Abbas, Abul K, Gratz, Iris K
Format: Article
Language:English
Subjects:
Animals
Autoimmune Diseases - immunology
Autoimmune Diseases - pathology
Cell Differentiation - immunology
Disease Models, Animal
Forkhead Transcription Factors - metabolism
Humans
Lymphocyte Activation
Mice
Mice, Transgenic
Ovalbumin - genetics
Ovalbumin - immunology
Receptors, Antigen, T-Cell - metabolism
Signal Transduction - drug effects
Signal Transduction - immunology
Sirolimus - pharmacology
Skin - immunology
Skin - pathology
T-Lymphocyte Subsets - immunology
T-Lymphocyte Subsets - metabolism
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - metabolism
TOR Serine-Threonine Kinases - antagonists & inhibitors
TOR Serine-Threonine Kinases - metabolism
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Summary:Immune homeostasis in peripheral tissues is, to a large degree, maintained by the differentiation and action of regulatory T cells (Treg) specific for tissue Ags. Using a novel mouse model, we have studied the differentiation of naive CD4 T cells into Foxp3 Treg in response to a cutaneous Ag (OVA). We found that expression of OVA resulted in fatal autoimmunity and in prevention of peripheral Treg generation. Inhibiting mTOR activity with rapamycin rescued the generation of Foxp3 T cells. When we varied the level of Ag expression to modulate TCR signaling, we found that low Ag concentrations promoted the generation of Foxp3 T cells, whereas high levels expanded effector T cells and caused severe autoimmunity. Our findings indicate that the expression level of tissue Ag is a key determinant of the balance between tissue-reactive effector and peripheral Foxp3 T cells, which determines the choice between tolerance and autoimmunity.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1901094