Well, for my comic, POW! Right in the Nostalgia, I have done a number of things interaction wise with people. (Mainly on Comic Fury though since that is where my comic has been hosted for a few years.)
I had trivia quizzes about retro stuff that people would answer and the one with the most questions answered right would win a free drawing of their choice.
I've also reached to people for guest comics or art during times I needed to rest a bit.
I also held a character design contest for a band in which people placed entries for the various positions of the band (guitarist, drummer, etc), and once the deadline hit, I had everyone vote on which design they liked best. The winners were then incorporated into the comic.
Otherwise, I always make an attempt to respond to everyone that posts comments in my comic. I particular enjoy the comments where someone is all "I remember this" when I focus on something like maybe a toy from the 90s, or an old video game not many recall...and so on...