O'Keeffe has been appointed to referee Wales v Scotland in Cardiff on February 3 with Doleman and Mabey, his assistant referees, and Pickerill in the TMO box.
On the same day, Williams will referee Italy v England in Rome.
A week later, Doleman will whistle the England v Wales game at Twickenham with O'Keeffe as one of his assistant referees with Pickerill TMO. Joining them as an assistant referee will be the first woman to have a role in the competition, Scottish referee Hollie Davidson.
The tournament is the start of a new four-year cycle, and World Rugby's director of rugby Phil Davies, said they were working with unions to create greater opportunities to identify and develop the next generation of match officials.
"This selection reflects that commitment while also retaining the experience that underpins the DNA of modern refereeing. We are also committed to collaborating with international coaches and players to ensure that we shape the future of officiating."
Three referees will make their debuts during the tournament, while eight referees, including Mabey, are being introduced as assistant referees.
