Eric Dier will captain a side that is likely to include goalkeeper Jack Butland, defenders James Tarkowski, Kyle Walker and Danny Rose, midfielders Ruben Loftus-Cheek and Fabian Delph, plus striker Danny Welbeck.
It is a situation Southgate is uncomfortable with as he looks to build on the success of the summer in Russian Federation when his Three Lions reached the World Cup semi-finals.
Although Kane top-scored at the World Cup with six goals and has two from four games in the Premier League this season, there have been question marks over his overall levels of performance with some pundits suggesting that his drop in shot attempts per game highlights his fatigue. Over at Old Trafford, however, he has only managed three goals since March.
Southgate said: "I think there are lots of different situations for them".
"We gave them a bit too much respect with the ball". "So numerous lads were playing their first 45 minutes of the season", he said.
We know all about the influx of foreign players into the Premier League and how the selection pool is becoming ever smaller to pick from. The 20-year-old is set to score this season for the club and was sent off last time out against Burnley.
England struggled to get Loftus-Cheek on the ball in unsafe positions in the first half and when they did, he was unable to do much with it, often showing an inability to turn when presented with the ball with his back to goal.
"We are going to have to assess that each time". I was at the Manchester City versus Huddersfield game and you think, 'well ok, it is a game where Foden will play'.
The game was also a reminder of just how unbearable the England band are.
So, take a look at the slideshow above to see which players we feel were fortunate to wear the three lions as one of England's elite.