The diversity of costimulatory and inhibitory receptor pathways and the regulation of antiviral T cell responses

Abstract

T cell responses are regulated by integrating positive and negative signals from costimulatory and inhibitory receptors. While the function of specific T cell costimulatory molecules during infections has been appreciated for some time, recent observations have now revealed a crucial role for inhibitory receptors in regulating T cell responses to pathogens, especially during chronic infections. A key emerging principle is that there is considerable diversity in the number and type of inhibitory receptors that can be expressed by T cells during both acute and chronic infections. These distinct inhibitory pathways appear to cooperate in regulating T cell function, could have distinct mechanisms of action, and are likely to provide novel therapeutic targets during persisting infections and other diseases.

Figure 1

Model showing possible mechanisms of T cell regulation by inhibitory receptors. Model 1: Both TCR-mediated signals and costimulation are inhibited by inhibitory receptors resulting in a termination or quantitative reduction in gene transcription. Model 2: Only some of the TCR and costimulatory-induced signals are inhibited resulting in qualitatively altered gene transcription. Model 3: Inhibitory receptors may regulate some costimulatory pathways while allowing others to signal normally resulting in qualitatively different costimulatory signals. Model 4: Inhibitory receptor signaling could block costimulation-induced signaling and partially block TCR signaling but also induce the transcription of novel genes.

Figure 1

Model showing possible mechanisms of T cell regulation by inhibitory receptors. Model 1: Both TCR-mediated signals and costimulation are inhibited by inhibitory receptors resulting in a termination or quantitative reduction in gene transcription. Model 2: Only some of the TCR and costimulatory-induced signals are inhibited resulting in qualitatively altered gene transcription. Model 3: Inhibitory receptors may regulate some costimulatory pathways while allowing others to signal normally resulting in qualitatively different costimulatory signals. Model 4: Inhibitory receptor signaling could block costimulation-induced signaling and partially block TCR signaling but also induce the transcription of novel genes.

Figure 1

Model showing possible mechanisms of T cell regulation by inhibitory receptors. Model 1: Both TCR-mediated signals and costimulation are inhibited by inhibitory receptors resulting in a termination or quantitative reduction in gene transcription. Model 2: Only some of the TCR and costimulatory-induced signals are inhibited resulting in qualitatively altered gene transcription. Model 3: Inhibitory receptors may regulate some costimulatory pathways while allowing others to signal normally resulting in qualitatively different costimulatory signals. Model 4: Inhibitory receptor signaling could block costimulation-induced signaling and partially block TCR signaling but also induce the transcription of novel genes.

Figure 1

Model showing possible mechanisms of T cell regulation by inhibitory receptors. Model 1: Both TCR-mediated signals and costimulation are inhibited by inhibitory receptors resulting in a termination or quantitative reduction in gene transcription. Model 2: Only some of the TCR and costimulatory-induced signals are inhibited resulting in qualitatively altered gene transcription. Model 3: Inhibitory receptors may regulate some costimulatory pathways while allowing others to signal normally resulting in qualitatively different costimulatory signals. Model 4: Inhibitory receptor signaling could block costimulation-induced signaling and partially block TCR signaling but also induce the transcription of novel genes.