Harmon explained that her character Jane will be shocked when she discovers that Maura (Sasha Alexander) has been hiding a big secret.
The actress added that the revelation will cause Jane to reassess her friendship with Maura.
"Jane comes to the realisation that she's maybe misjudged her relationship with Maura," Harmon told TV Guide. "She's always thought she could be herself and be personal around Maura, and the way Maura is acting is proving that to be untrue."
Harmon and Alexander recently denied speculation that Rizzoli and Isles have a lesbian relationship.
The second season, which will feature appearances from stars including Ed Begley Jr, Chris Vance and Bill O'Reilly, will premiere on July 11 at 10/9c on TNT.
Watch a trailer for season two of Rizzoli & Isles below: