IMMUNOLOGY
Signaling Strength Determines T Cell Fate
Mature T cells may have either an αβ T cell receptor (αβ TCR) or a 
TCR. Cells expressing either receptor type can specify the αβ lineage, which produces CD4+ and CD8+ T cells (as distinct from the lineage, which remains CD4–/CD8–) (see Robey). Hayes et al. and Haks et al. provide evidence supporting a quantitative model for T cell fate specification, which provides a mechanism for how the different receptor complexes can produce cells of either fate. Both groups report that a weak signal produced by the TCR can result in specification of the αβ lineage. Hayes et al. relied on transgenic mice in which the TCR signaling was manipulated. In cells in which the TCR abundance at the cell surface was decreased, there was an increase in the number of cells adopting the αβ fate [CD4+/CD8+ or double positive (DP)]. Conditions that increased TCR abundance decreased the number of DP cells. Mice were genetically engineered to produce TCR complex with different numbers of immunoreceptor tyrosine-based activation motifs (ITAMs). Mice expressing a four-ITAM TCR complex reduced the number of T cells but did not increase the number of αβ cells. Mice expressing a six-ITAM TCR complex produced an increased number of αβ cells at the expense of the cells. Mice deficient for the negative regulator CD5 also produced fewer αβ cells, consistent with the model that weak signaling promotes the αβ lineage. Haks et al. used a transgenic mouse in which the TCR was engineered to recognize a specific antigen, the KN6 TCR. Mice were further engineered to inhibit production of the ligand for the KN6 TCR, and the abundance of cells was decreased whereas the abundance of DP cells was increased. Activation of the extracellular signal-regulated kinases (ERK1 and ERK2) was greater, as was induction of the ERK target EGR genes, in cells that adopted the fate, compared with cells in which TCR signaling was impaired through Lck deficiency or reduced KN6 TCR ligand. Overexpression of egr1 forced the adoption of the fate at the expense of αβ cells both in wild-type cells and in cells in which TCR signaling was impaired. The EGR target Id3 was not sufficient to drive cell fate, but was necessary, because Id3-deficient cells did not adopt the fate in response to overexpression of egr1. The results of these two groups provide a mechanistic explanation for the cross-lineage specification of αβ cells by cells and support the quantitative model of cell fate specification.
E. Robey, The αβ versus T cell fate decision: When less is more. Immunity 22, 533-534 (2005). [PubMed]
S. M. Hayes, L. Li, P. E. Love, TCR signal strength influences αβ/ lineage fate. Immunity 22, 583-593 (2005). [PubMed]
M. C. Haks, J. M. Lefebvre, J. P. H. Lauritsen, M. Carleton, M. Rhodes, T. Miyazaki, D. J. Kappes, D. L. Wiest, Attenuation of TCR signaling efficiently diverts thymocytes to the αβ lineage. Immunity 22, 595-606 (2005). [PubMed]
