title: A 175 million year history of T cell regulatory molecules reveals widespread selection, with adaptive evolution of disease alleles.
abstract: T cell activation plays a central role in immune response and in the maintenance of self-tolerance. We analyzed the evolutionary history of T cell regulatory molecules. Nine genes involved in triggering T cell activation or in regulating the ensuing response evolved adaptively in mammals. Several positively selected sites overlap with positions interacting with the binding partner or with cellular components. Population genetic analysis in humans revealed a complex scenario of local (FASLG, CD40LG, HAVCR2) and worldwide (FAS, ICOSLG) adaptation and H. sapiens-to-Neandertal gene flow (gene transfer between populations). Disease variants in these genes are preferential targets of pathogen-driven selection, and a Crohn's disease risk polymorphism targeted by bacterial-driven selection modulates the expression of ICOSLG in response to a bacterial superantigen. Therefore, we used evolutionary information to generate experimentally testable hypotheses concerning the function of specific genetic variants and indicate that adaptation to infection underlies the maintenance of autoimmune risk alleles.
authors.affiliation: Scientific Institute IRCCS E. Medea, 23842 Bosisio Parini, LC, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Forni
authors.forename: Rachele
authors.initials: R
authors.lastname: Cagliani
authors.forename: Uberto
authors.initials: U
authors.lastname: Pozzoli
authors.forename: Marta
authors.initials: M
authors.lastname: Colleoni
authors.forename: Stefania
authors.initials: S
authors.lastname: Riva
authors.forename: Mara
authors.initials: M
authors.lastname: Biasin
authors.forename: Giulia
authors.initials: G
authors.lastname: Filippi
authors.forename: Luca
authors.initials: L
authors.lastname: De Gioia
authors.forename: Federica
authors.initials: F
authors.lastname: Gnudi
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Comi
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
authors.forename: Manuela
authors.initials: M
authors.lastname: Sironi
mesh_terms: D000222:Adaptation, Physiological; D000483:Alleles; D000818:Animals; D001327:Autoimmune Diseases / Q000453:epidemiology / Q000235:genetics / Q000276:immunology*; D005075:Biological Evolution; D051456:Gene Flow; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D059125:Neanderthals; D020641:Polymorphism, Single Nucleotide; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics*; D012306:Risk; D012641:Selection, Genetic; D017634:Self Tolerance / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor