title: Reduced TCR signaling potential impairs negative selection but does not result in autoimmune disease.
abstract: Negative selection and regulatory T (T reg) cell development are two thymus-dependent processes necessary for the enforcement of self-tolerance, and both require high-affinity interactions between the T cell receptor (TCR) and self-ligands. However, it remains unclear if they are similarly impacted by alterations in TCR signaling potential. We generated a knock-in allele (6F) of the TCR ζ chain gene encoding a mutant protein lacking signaling capability whose expression is controlled by endogenous ζ regulatory sequences. Although negative selection was defective in 6F/6F mice, leading to the survival of autoreactive T cells, 6F/6F mice did not develop autoimmune disease. We found that 6F/6F mice generated increased numbers of thymus-derived T reg cells. We show that attenuation of TCR signaling potential selectively impacts downstream signaling responses and that this differential effect favors Foxp3 expression and T reg cell lineage commitment. These results identify a potential compensatory pathway for the enforcement of immune tolerance in response to defective negative selection caused by reduced TCR signaling capability.
authors.affiliation: Program on Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Sujin
authors.initials: S
authors.lastname: Hwang
authors.forename: Ki-Duk
authors.initials: KD
authors.lastname: Song
authors.forename: Renaud
authors.initials: R
authors.lastname: Lesourne
authors.forename: Jan
authors.initials: J
authors.lastname: Lee
authors.forename: Julia
authors.initials: J
authors.lastname: Pinkhasov
authors.forename: Liqi
authors.initials: L
authors.lastname: Li
authors.forename: Dalal
authors.initials: D
authors.lastname: El-Khoury
authors.forename: Paul E
authors.initials: PE
authors.lastname: Love
mesh_terms: D000483:Alleles; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D016026:Bone Marrow Transplantation / Q000276:immunology; D060966:Clonal Selection, Antigen-Mediated / Q000235:genetics / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D023061:Gene Order; D018398:Homeodomain Proteins / Q000235:genetics; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D060168:Thymocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018398:Homeodomain Proteins; D011948:Receptors, Antigen, T-Cell; C064658:RAG-1 protein