Co‐Stimulation and Co‐Inhibition: Equal Partners in Regulation

Abstract

Specific immune responses are controlled by two counterbalancing mechanisms-co-stimulation and co-inhibition. Antigen receptors determine specificity, activate co-stimulation and/or co-inhibition, and interact with these co-stimulatory/co-inhibitory mechanisms to dictate the direction of the immune response, either positive or negative. Co-stimulatory or co-inhibitory ligands interact with their specific receptors and may indicate the context in which antigen is perceived by lymphocytes. Ligation of antigen receptors may activate only co-stimulatory or co-inhibitory mechanisms, and thus may influence secondarily the direction of the immune response. Furthermore, the activity of a given co-stimulator or co-inhibitory receptor is modified depending on signalling via the antigen receptor. If neither co-stimulators nor co-inhibitors are present, lymphocytes, activated in response to antigen receptor signalling, produce low levels of effector elements and then revert to inactivity. Co-inhibitors are defective in autoimmune disease.

Time, Space and Contextual Models of the Immunity Tolerance Decision: Bridging the Geographical Divide of Zinkernagel and Hengartner's ‘Credo 2004’

“…Also, since the efficiency of central tolerance, even for high-affinity antiself T-cell receptors (TCR) is not 100%, this mechanism would also allow tolerance in these low-frequency high-affinity escapees. Thus, I do not consider the importance of tolerance in the periphery due to persistent widely distributed self-antigen in serious doubt (we have also postulated the importance of widely distributed persistent antigen [24,25]), but that this mechanism is not, as Z&H propose, the equivalent of or equal in importance to the central tolerance mechanism.…”

“…In addition to costimulation, a high-precursor frequency of responding cells, through cellular collaboration (T cell help), could also contribute to tipping the balance away from coinhibition-mediated tolerance in favour of immunity or a state that appears like ignorance. Chronic antigen-receptor signalling, as would occur with widespread high-dose antigens, is instead postulated to favour coinhibition [24]. Furthermore, the ability of activating receptors to work with negative coreceptors to generate an inactivating signal, a mechanism postulated 35 years ago [26] that we termed coinhibition [24], is also key in controlling innate immunity.…”

“…Chronic antigen-receptor signalling, as would occur with widespread high-dose antigens, is instead postulated to favour coinhibition [24]. Furthermore, the ability of activating receptors to work with negative coreceptors to generate an inactivating signal, a mechanism postulated 35 years ago [26] that we termed coinhibition [24], is also key in controlling innate immunity.…”

The MHC-Based Suppression (MBS) Theory: Implications for Transplantation

“…Naive T cells tend to respond to inhibitory signaling by becoming anergic, and this is reversible [17] whilst armed effector cells respond to the same stimuli by either apoptosis or, if they survive, then become active regulatory cells, able to inhibit a new influx of primed antigen-specific cells; this state is not reversible [17]. The concept of co-inhibition was introduced more than 10 years ago [24,25], and has slowly expanded . The term now includes signaling via CD152-mediated inhibition of CD28, by competitive binding of CD80/CD86, signaling via PD1/PD1 ligand, and production of inhibitory cytokines, such as IL 10 and TGF-beta.…”

Coinhibitory T-Cell Signaling in Islet Allograft Rejection and Tolerance

“…The identified Ig superfamily members, of which include inhibitory B7-recognizor, in some cases, induce anergy or tolerance (92). The idea of cosignaling molecules in lymphocyte activation ing receptors [cytotoxic T lymphocyte-associated antigen-4 (CTLA-4, CD152), programmed death-1 (PD-1)] was first described as part of the "tripartite inactivation model" in 1971 (106), and expanded upon in subsequent and TNFR-recognizing inhibitory receptor BTLA, are expressed on activated lymphocytes, and thus regulate years to include costimulators (50) and coinhibitors (105). Discovery of new coinhibitory pathways adds an ongoing immune responses in lymphoid tissue and the periphery.…”