CD28 and Autoimmunity: The positive regulatory co-receptors CD28 and inducible co-stimulator (ICOS) transduce stimulatory co-signals, whereas the negative regulatory co-stimulators CTLA-4 and PD-1 are critical for the regulation of peripheral tolerance and autoimmunity (Nishimura et al. 1999; Shi et al. 2016).