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A hierarchy of T<\/jats:styled-content>\u2010cell activation by MHC<\/jats:styled-content> class I\u2010restricted altered peptide ligands has been defined using the T<\/jats:styled-content>\u2010cell receptor P14 specific for H\u20102D<\/jats:styled-content>b<\/jats:sup> in complex with the immunodominant lymphocytic choriomeningitis virus peptide gp33 (KAVYNFATM<\/jats:styled-content>). While substitution of tyrosine to phenylalanine (Y<\/jats:styled-content>4F<\/jats:styled-content>) or serine (Y<\/jats:styled-content>4S<\/jats:styled-content>) abolished recognition by P<\/jats:styled-content>14, the TCR<\/jats:styled-content> unexpectedly recognized H<\/jats:styled-content>\u20102D<\/jats:styled-content>b<\/jats:sup> in complex with the alanine\u2010substituted semiagonist Y<\/jats:styled-content>4A<\/jats:styled-content>, which displayed the most significant structural modification. The observed functional hierarchy gp33 > Y<\/jats:styled-content>4A<\/jats:styled-content> > Y<\/jats:styled-content>4S<\/jats:styled-content> = Y<\/jats:styled-content>4F<\/jats:styled-content> was neither due to higher stabilization capacity nor to differences in structural conformation. However, thermodynamic analysis demonstrated that while recognition of the full agonist H<\/jats:styled-content>\u20102D<\/jats:styled-content>b<\/jats:sup>\/gp33 was strictly enthalpy driven, recognition of the weak agonist H<\/jats:styled-content>\u20102D<\/jats:styled-content>b<\/jats:sup>\/Y<\/jats:styled-content>4A<\/jats:styled-content> was instead entropy driven with a large reduction in the favorable enthalpy term. The fourfold larger negative heat capacity derived for the interaction of P<\/jats:styled-content>14 with H<\/jats:styled-content>\u20102D<\/jats:styled-content>b<\/jats:sup>\/gp33 compared with H<\/jats:styled-content>\u20102D<\/jats:styled-content>b<\/jats:sup>\/Y<\/jats:styled-content>4A<\/jats:styled-content> can possibly be explained by higher water entrapment at the TCR<\/jats:styled-content>\/MHC<\/jats:styled-content> interface, which is also consistent with the measured opposite entropy contributions for the interactions of P<\/jats:styled-content>14 with both MHC<\/jats:styled-content>s. In conclusion, this study demonstrates that P<\/jats:styled-content>14 makes use of different strategies to adapt to structural modifications in the MHC<\/jats:styled-content>\/peptide complex.<\/jats:p>","DOI":"10.1002\/eji.201242588","type":"journal-article","created":{"date-parts":[[2012,7,26]],"date-time":"2012-07-26T14:51:55Z","timestamp":1343314315000},"page":"2990-3000","source":"Crossref","is-referenced-by-count":14,"title":["Unexpected T<\/scp>\u2010cell recognition of an altered peptide ligand is driven by reversed thermodynamics"],"prefix":"10.1002","volume":"42","author":[{"given":"Eva B.","family":"Allerbring","sequence":"first","affiliation":[{"name":"Center for Infectious Medicine (CIM) Department of Medicine Karolinska University Hospital Huddinge Karolinska Institutet Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adil D.","family":"Duru","sequence":"additional","affiliation":[{"name":"Center for Infectious Medicine (CIM) Department 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