title: Strength of TCR signal from self-peptide modulates autoreactive thymocyte deletion and Foxp3(+) Treg-cell formation.
abstract: Autoreactive CD4(+) CD8(-) (CD4SP) thymocytes can be subjected to deletion when they encounter self-peptide during their development, but they can also undergo selection to become CD4SPFoxp3(+) Treg cells. We have analyzed the relationship between these distinct developmental fates using mice in which signals transmitted by the TCR have been attenuated by mutation of a critical tyrosine residue of the adapter protein SLP-76. In mice containing polyclonal TCR repertoires, the mutation caused increased frequencies of CD4SPFoxp3(+) thymocytes. CD4SP thymocytes expressing TCR Vβ-chains that are subjected to deletion by endogenous retroviral superantigens were also present at increased frequencies, particularly among Foxp3(+) thymocytes. In transgenic mice in which CD4SP thymocytes expressing an autoreactive TCR undergo both deletion and Treg-cell formation in response to a defined self-peptide, SLP-76 mutation abrogated deletion of autoreactive CD4SP thymocytes. Notably, Foxp3(+) Treg-cell formation still occurred, albeit with a reduced efficiency, and the mutation was also associated with decreased Nur77 expression by the autoreactive CD4SP thymocytes. These studies provide evidence that the strength of the TCR signal can play a direct role in directing the extent of both thymocyte deletion and Treg-cell differentiation, and suggest that distinct TCR signaling thresholds and/or pathways can promote CD4SP thymocyte deletion versus Treg-cell formation.
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Caton
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kropf
authors.forename: Donald M
authors.initials: DM
authors.lastname: Simons
authors.forename: Malinda
authors.initials: M
authors.lastname: Aitken
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Weissler
authors.forename: Martha S
authors.initials: MS
authors.lastname: Jordan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology*; D015551:Autoimmunity; D017637:Clonal Deletion / Q000235:genetics / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015870:Gene Expression; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009154:Mutation; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D060168:Thymocytes / Q000276:immunology* / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001324:Autoantigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D010455:Peptides; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; C092947:SLP-76 signal Transducing adaptor proteins
keywords: Immune regulation; Thymic selection; Tolerance