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

• 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
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1901094

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.