Tonic Signals: Why Do Lymphocytes Bother?

Since the 1990s it has been known that B and T lymphocytes exhibit low-level, constitutive signaling in the basal state (tonic signaling). These lymphocytes display a range of affinity for self, which in turn generates a range of tonic signaling. Surprisingly, what signaling pathways are active in the basal state and the functional relevance of the observed tonic signaling heterogeneity remain open questions today. Here we summarize what is known about the mechanistic and functional details of tonic signaling. We highlight recent advances that have increased our understanding of how the amount of tonic signal impacts immune function, describing novel tools that have moved the field forward and toward a molecular understanding of tonic signaling. T and B lymphocytes exhibit low level, constitutive signaling in the basal state (tonic signaling). Tonic signals are essential for the survival of B cells, whereas the functional role of tonic signals in T cells is still being worked out. Surface CD5 expression levels as well as the genetic Nur77–eGFP reporter are tools that have recently been exploited as markers of affinity for self- and tonic signaling. B and T cells exhibit a range of self-reactivity in the basal state. Tonic signals in CD4 and CD8 T cells serve a maintenance function, and cells with high tonic signals perform better in an immune response. Tonic signals in regulatory T cells are critical for their suppressive capacity. Mouse models with single point mutations in signaling molecules display altered tonic signals and autoimmune features and have aided mapping of tonic signaling pathways in T cells.