Joe Schmidt has left captain Rory Best and vice-captain Johnny Sexton out of his squad for Ireland's opening autumn Test against Italy in Chicago.
A reduced 26-man squad travels to the US on Monday with several of Schmidt's most experienced players rested.
Peter O'Mahony, Rob Kearney and Keith Earls are among the other names to be left at home.
Ireland take on Argentina, New Zealand and the USA in consecutive weeks at the Aviva Stadium following the Italy Test.
Best is one of four Ulster players to have been named in the initial 42-man squad who will not travel to Chicago for the game on 3 November along with Iain Henderson, Rob Herring and Stuart McCloskey.
Half-back spots up for grabs
Uncapped Leinster fly-half Ross Byrne will compete with Joey Carbery for the number 10 jersey in Sexton's absence.
With Sexton assured of his place as first choice fly-half the Italy game is likely to give some indication as to who will deputise for the Leinster captain in the games against Argentina and reigning world champions New Zealand.
Connacht's Kieran Marmion will not travel meaning John Cooney and Luke McGrath will vie for the starting scrum-half berth.
There has been much debate around who will occupy the number nine shirt for the All Blacks Test given that Conor Murray remains sidelined with a neck injury.
Marmion can call on the most international experience with 22 caps while McGrath is used to operating in tandem with Sexton at provincial level.
Cooney picked up Ulster's Player of the Season award at the end of the 2017-18 campaign after a fine debut season at the Kingspan Stadium.
New-look back three
Kearney and Earls were ever-presents for Schmidt in an historic 2017 in which Ireland landed the Grand Slam and a first series victory over Australia for 39 years.
Utility back Will Addison will be hoping to earn his first cap against Italy with Jacob Stockdale, Jordan Larmour and Munster duo Andrew Conway and Darren Sweetnam all in contention to start in the back three.
Italy head coach Conor O'Shea has already named his team for the Test at Soldier Field, the venue in which Ireland defeated New Zealand for the first time in 2016.
Ireland squad for Italy Test in Chicago
Forwards: F Bealham (Connacht), T Beirne (Munster), J Conan (Leinster), S Cronin (Leinster), T Furlong (Leinster), D Kilcoyne (Munster), Jack McGrath (Leinster), J Murphy (Ulster), A Porter (Leinster), Q Roux (Connacht), R Ruddock (Leinster), James Ryan (Leinster), N Scannell (Munster), D Toner (Leinster), J van der Flier (Leinster).
Backs: W Addison (Ulster), A Conway (Munster), D Sweetnam (Munster), J Larmour (Leinster), J Stockdale (Ulster), G Ringrose (Leinster), B Aki (Connacht), R Byrne (Leinster), J Carbery (Munster), J Cooney (Ulster), L McGrath (Leinster).