Maintaining immune tolerance is a dynamic biological process which is provided by various types of tolerance mechanisms. In the light of the remarkable role of co-inhibitory receptors for switching-off the immune system, the potential impact of these receptors in controlling auto-reactivity is needed to be interrogated. Recent investigations suggested that the dysregulation of co-inhibitory receptors in chronic immune responses including cancer and chronic infections can result in immunological consequences called exhaustion. Exhaustion confer a potent “switch-off” mechanism for immune response. Using both co-inhibitory receptors and transcription factors in controlling T cells behavior, this review provide an overview of the potential effects of co-inhibitory receptors in maintaining tolerance and discuss how impaired co-inhibitory receptors might results in autoimmunity.