Harry Maguire and Jude Bellingham were both picked to start for England on Friday against Italy.
Maguire hasn't started a Premier League game for Manchester United in the last six weeks, but is still seen by Gareth Southgate as a key leader of England's defence.
The England manager, however, decided to provide Maguire with extra cover, and start with three centre-backs in the San Siro. He is joined by Tottenham's Eric Dier and Man City's Kyle Walker at the heart of defence.
Arsenal forward Bukayo Saka was selected as left wing-back, with Chelsea's Reece James on the other flank.
Southgate elected to start with an attacking trident of Man City's Phil Foden, Spurs' Harry Kane and Chelsea's Raheem Sterling.
With Kalvin Phillips due to undergo shoulder surgery and Jordan Henderson still recovering from a hamstring strain, Bellingham was given the chance to impress in the Nations League tonight, alongside Declan Rice.
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The 19-year-old has been in outstanding form in Germany, and has started all 10 games for Borussia Dortmund this season in the Bundesliga, Champions League and German Cup.
Henderson is ahead of schedule in his recovery from a hamstring strain, and while he won't play against Italy, Southgate is hopeful he will be fit enough to feature against Germany at Wembley on Monday.
Brentford striker Ivan Toney is not in the matchday squad along with Ben Chilwell, Marc Guehi, the suspended John Stones and Henderson.
Analysis: Bellingham form demanded starting berth
Sky Sports News senior reporter Rob Dorsett:
"This is his fifth start for England but a 16th cap which is extraordinary when you consider he's still only 19 years old. He's been involved in the England set up since he was 17 - when he was first called up under Southgate.
"His influence, his abilities and his confidence has grown in the last two years both for Borussia Dortmund and for England.
"His form for Dortmund demands that he starts tonight, in truth. He's played more games this season than any other player in this England squad - 10 games in the Bundesliga, in the Champions League and the German Cup. He's started every match for Dortmund and scored three goals.
"When you consider Kalvin Phillips withdrew from this squad and is set to undergo shoulder surgery, Jordan Henderson is in this squad but is recovering from a hamstring strain, I think it was looking increasingly likely Bellingham would get his chance.
"Starting Maguire, however, is a controversial call given his lack of football with Manchester United."
Southgate 'throws support behind Maguire'
The Guardian's Manchester football correspondent Jamie Jackson told Sky Sports:
"It's not a surprise to see Gareth Southgate come out in support of Harry Maguire as he's been impeccable for England.
"He was in the side which took England to a World Cup semi-final and the final of the European Championship.
"He's lost his place at Manchester United. It was a big call from Erik ten Hag but it's not too surprising. I did think it would be Raphael Varane and Lisandro Martinez as first choice.
"Southgate is saying it's OK as it's only a few games after pre-season. He did say it could become a problem if he doesn't have much game time between now and the World Cup.
"But I don't see him getting back into the team. With this three-man defence that Gareth likes to play, I still think that even if Maguire doesn't get back into the United side, I feel he will be first choice for the World Cup."
Nations League state of play: England in trouble?
When A3 was drawn, Hungary quickly appeared to be the favourites to finish bottom of this highly-competitive group, but Marco Rossi's side have collected seven points from their first four games and currently sit top of the table.
Hungary's most recent fixture saw them pull off a shock 4-0 win over England at Wembley in June. Their game against Germany in Leipzig on Friday will be crucial, with the winners knowing another victory on the final matchday on Monday will guarantee them a spot in the finals.
Italy are just two points behind Hungary and face them in Budapest next week, meaning the European champions are very much still in contention in Group A3.
The only team that cannot reach the finals are England, who are winless and face a tough task to avoid the ignominy of relegation to League B for the first time.
Defeat to Italy on Friday will confirm relegation for Gareth Southgate's team, who realistically must win in Milan and at home to Germany on Monday if they want to stay up.
England's World Cup Group B fixtures
November 21: Iran (Khalifa International Stadium, Al Rayyan) - kick-off 1pm
November 25: USA (Al Bayt Stadium, Al Khor) - kick-off 7pm
November 29: Wales (Ahmed bin Ali Stadium, Al Rayyan) - kick-off 7pm
Pick your England starting XI for World Cup 2022
Gareth Southgate has unveiled his final pre-World Cup England squad - but who would make your starting XI?
What would your England starting XI look like if the World Cup started today and all players were available? Use our interactive selector to pick your team below, screenshot your selections and share on Twitter @SkyFootball.
(c) Sky Sports 2022: Jude Bellingham and Harry Maguire start for England against Italy in Nations League