A 175 Million Year History of T Cell Regulatory Molecules Reveals Widespread Selection, with Adaptive Evolution of Disease Alleles

Diego Forni, Rachele Cagliani, Uberto Pozzoli, Marta Colleoni, Stefania Riva, Mara Biasin, Giulia Filippi, Luca DeGioia, Federica Gnudi, GiacomoP Comi, Nereo Bresolin, Mario Clerici, Manuela Sironi

Research output: Contribution to journalArticlepeer-review

Abstract

T cell activation plays a central role in immune response and in the maintenance of self-tolerance. We analyzed the evolutionary history of Tcell regulatory molecules. Nine genes involved in triggering Tcell 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 acomplex 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.

Original languageEnglish
Pages (from-to)1129-1141
Number of pages13
JournalImmunity
Volume38
Issue number6
DOIs
Publication statusPublished - Jun 27 2013

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases
  • Immunology

Fingerprint Dive into the research topics of 'A 175 Million Year History of T Cell Regulatory Molecules Reveals Widespread Selection, with Adaptive Evolution of Disease Alleles'. Together they form a unique fingerprint.

Cite this