George Ford, Owen Farrell and Manu Tuilagi will start in midfield for the first time under Steve Borthwick in England's World Cup clash against Samoa.
Ford and Farrell will combine as dual playmakers in Lille on Saturday in the final round of Pool D action.
Sale creator Ford will start at fly-half, with Saracens talisman Farrell captaining England from inside centre.
Head coach Borthwick will pair Ford and Farrell together from the start in an experienced 10-12 axis for the first time since taking the England helm in December.
Tuilagi will face his country of birth for the first time in his career when starting at outside centre. The 32-year-old Sale star will be pumped up for a proud and emotional day, both for himself and his family.
England have already qualified for the quarter-finals with a pool game to spare, but will be at full-strength against former London Irish centre Seilala Mapusua's potent Samoa side.
Ford and Farrell have been operating in tandem at 10 and 12 for England teams dating all the way back to the Under-16s. Half their lives later, Ford with 88 caps and 30 years old, and 32-year-old Farrell, boasting 108 caps, are back together as an inside-back duo.
The set-up thrived as England reached the 2019 World Cup Final in Japan, and Borthwick will now look to reprise that fluency four years down the line.
Saracens back-row forward Ben Earl hailed Farrell as captain and talisman, while praising Ford for leading England's attacking blueprint.
"I have played with Owen a lot more than George, but I have also played with George a fair amount," said Earl. "They bring slightly different skill-sets, but complement each other very well, whether they start together or one comes off the bench.
"George is very good at manipulating defences, short-side attack, changing lanes, putting lads through holes out the back, whereas Owen is a lot more physical, a lot more playing at the line.
"They are both great kickers of the ball, they both read the game very well, they are both great communicators. Having those similar, but slightly different skill-sets will only be good for us.
"They are both leaders in their own right: Owen leading the team as captain, George leading the attack. We have seen them both having magic moments already in this World Cup. Long may it continue."
Joe Marchant has forced his way into England's starting line-up on the wing, dislodging Elliot Daly. The Stade Francais-bound three-quarter will add pace, guile and the ability to operate as an auxiliary centre in England’s backline.
Tuilagi's 56th cap will double as his first against his homeland. The former Leicester wrecking-ball was born on the Pacific island, but moved to England aged nine to link up with his rugby star brothers.
Tuilagi arrived on a holiday visa and never left — and had to battle deportation threat before launching his storied rugby career with the Tigers.
Brothers Freddie, Andy, Alesana, Henry and Vavae have all represented Leicester, too, in one of rugby's biggest and toughest dynasties.
Nephew Posolo Tuilagi is now starring for Perpignan and France U-20s, a 19-year-old standing 6ft 5in and weighing at more than 140kg.
England's Tuilagi spoke proudly of his family ranks that were able to watch as the Red Rose men defeated Argentina 27-10 to open this World Cup campaign in style.
A long-awaited first clash against his homeland might be a momentous day for Tuilagi and his vast family, but England are confident his dual heritage will only bring out the best in their star centre.
"I see him as an Englishman; I understand he has that heritage, but I've got Scottish blood, and no one talks to me about how I feel about Scotland," said England defence coach Kevin Sinfield.
"We understand the heritage there, but I see him as English, so do I think it would affect his performance? Not one bit. If anything, we might get a little bit more from him, because he will want to make two countries proud."
England XV: Steward; Marchant, Tuilagi, Farrell (c), May; Ford, Mitchell; Genge, George, Cole; Itoje, Chessum, Lawes, Curry, Earl
Replacements: Dan, Marler, Sinckler, Martin, Vunipola, Care, Smith, Lawrence.
