title: Cutting edge: Lymphoproliferation caused by Fas deficiency is dependent on the transcription factor eomesodermin.
abstract: A hallmark of autoimmune lymphoproliferative syndrome (ALPS), caused by mutation of the Fas death receptor, is massive lymphadenopathy from aberrant expansion of CD4(-)CD8(-) (double-negative [DN]) T cells. Eomesodermin (Eomes) is a member of the T-box family of transcription factors and plays critical roles in effector cell function and memory cell fitness of CD8(+) T lymphocytes. We provide evidence in this study that DN T cells exhibit dysregulated expression of Eomes in humans and mice with ALPS. We also find that T cell-specific deletion of Eomes prevents lymphoid hypertrophy and accumulation of DN T cells in Fas-mutant mice. Although Eomes has critical physiological roles in the function and homeostasis of CD8(+) T cells, overexpression of Eomes appears to enable pathological induction or expansion of unusual CD8-related T cell subsets. Thus, antagonism of Eomes emerges as a therapeutic target for DN T cell ablation in ALPS.
authors.affiliation: Abramson Family Cancer Research Institute, Division of Infectious Diseases, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ichiko
authors.initials: I
authors.lastname: Kinjyo
authors.forename: Scott M
authors.initials: SM
authors.lastname: Gordon
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Intlekofer
authors.forename: Kennichi
authors.initials: K
authors.lastname: Dowdell
authors.forename: Erin C
authors.initials: EC
authors.lastname: Mooney
authors.forename: Roberto
authors.initials: R
authors.lastname: Caricchio
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
authors.forename: David T
authors.initials: DT
authors.lastname: Teachey
authors.forename: V Koneti
authors.initials: VK
authors.lastname: Rao
authors.forename: Tullia
authors.initials: T
authors.lastname: Lindsten
authors.forename: Steven L
authors.initials: SL
authors.lastname: Reiner
mesh_terms: D000818:Animals; D056735:Autoimmune Lymphoproliferative Syndrome / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D019014:fas Receptor
chemical_list: C491199:EOMES protein, human; C491198:Eomes protein, mouse; C491901:FAS protein, human; C491899:Fas protein, mouse; D020825:T-Box Domain Proteins; D019014:fas Receptor