title: TCR signaling by conventional CD4+T cells is required for optimal maintenance of peripheral regulatory T cell numbers.
abstract: To maintain immune tolerance, regulatory T cell (Treg) numbers must be closely indexed to the number of conventional T cells (Tconvs) so that an adequate Treg:Tconv ratio can be maintained. Two factors important in this process are the cytokine interleukin-2 (IL-2) and T cell receptor (TCR) stimulation by major histocompatibility complex class II (MHC-II). Here, we report that in addition to TCR stimulation of Tregs themselves, the maintenance of Tregs also requires TCR signaling by Tconvs. We found that Tconvs produce IL-2 in response to self-peptide-MHC-II complexes and that Tconvs possessing more highly self-reactive TCRs express more IL-2 at baseline. Furthermore, selective disruption of TCR signaling in Tconvs led to a trend toward decreased expression of IL-2 and attenuated their ability to maintain Treg numbers. These data suggest that in order to maintain an adequate Treg:Tconv ratio, Tregs are continuously indexed to self-peptide-MHC-II-induced TCR signaling of Tconvs. These results have implications in attempts to modulate immune tolerance, as Treg numbers adjust to the self-reactivity, and ultimately IL-2 production by the T cells around them.
authors.affiliation: Department of Pathology and Laboratory Medicine Perelman School of Medicine at the University of Pennsylvania Philadelphia PA 19104 USA.
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Leichner
authors.affiliation: First Department of Internal Medicine Kansai Medical University Moriguchi Osaka Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Satake
authors.affiliation: Department of Pathology and Laboratory Medicine Perelman School of Medicine at the University of Pennsylvania Philadelphia PA 19104 USA.
authors.forename: Taku
authors.initials: T
authors.lastname: Kambayashi
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D051858:Forkhead Transcription Factors; D007108:Immune Tolerance; D007376:Interleukin-2; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell
keywords: Homeostasis; IL‐2; indexing; regulatory T cell