I drive our 2005 E450 with it's 5-speed (6 gear ratios internally - with computer selection between two of them) Class C almost full time now with Tow/Haul mode engaged. Overdrive and cruise control still work in Tow/Haul mode and of course downhill automatic down-shifting happens all the time when in Tow/Haul mode whether in cruise control or not.
I find staying in Tow/Haul mode improves overall response and driveabilty under all conditions. However, this may be due to our Class C being relatively low in weight (24 feet @ ~11,800 lbs.) and built on the E450 chassis with it's low 4:56 rear differential ratio.