Cell surface signaling molecules in the control of immune responses: a tide model

Abstract

A large numbers of cell surface signaling molecules (CSSMs) have been molecularly identified and functionally characterized in recent years and, via these studies, our knowledge in the control of immune response has increased exponentially. Two major lines of evidence emerge. First, the majority of immune cells rely on one or few CSSMs to deliver a primary triggering signal to sense their environment, leading to initiation of an immune response. Second, both costimulatory CSSMs that promote the response, and coinhibitory CSSMs that inhibit the response, are required to control direction and magnitude of a given immune response. With such tight feedback, immune responses are tuned and returned to baseline. These findings extend well beyond our previous observation in the requirement for lymphocyte activation and argue a revisit of the traditional "two-signal model" for activation and tolerance of lymphocytes. Here we propose a "tide" model to accommodate and interpret current experimental findings.

Figure 1. The Tide Model for the Control of Immune Response

We define primary signal as a triggering signal or signals which initiate specific immune cell response to extracellular stimuli. The co-signals, which could be either costimulatory or coinhibitory, are modulator of signal one, and decide the direction and magnitude of a cellular reaction, leading to activation of naïve cells (Response), deactivation of already activated cells (De-response) or unresponsiveness (Un-response).

Figure 2. Cell surface signaling molecules in the control of immune responses

Primary signal and co-signals (co-stimulatory or co-inhibitory) are defined in each immune cell type. TLR, Toll-Like Receptor; RLR, RIG-like Receptors; NLR, NOD-like Receptor.