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Sci. STKE, 24 May 2005
Vol. 2005, Issue 285, p. tw197
[DOI: 10.1126/stke.2852005tw197]

EDITORS' CHOICE

IMMUNOLOGY Signaling Strength Determines T Cell Fate

Mature T cells may have either an αβ T cell receptor (αβ TCR) or a {gamma}{delta} TCR. Cells expressing either receptor type can specify the αβ lineage, which produces CD4+ and CD8+ T cells (as distinct from the {gamma}{delta} 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 {gamma}{delta} TCR can result in specification of the αβ lineage. Hayes et al. relied on transgenic mice in which the {gamma}{delta} TCR signaling was manipulated. In cells in which the {gamma}{delta} 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 {gamma}{delta} 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 {gamma}{delta} 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 {gamma}{delta} 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 {gamma}{delta} 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 {gamma}{delta} 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 {gamma}{delta} 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 {gamma}{delta} 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 {gamma}{delta} cell fate, but was necessary, because Id3-deficient cells did not adopt the {gamma}{delta} 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 {gamma}{delta} cells and support the quantitative model of cell fate specification.

E. Robey, The αβ versus {gamma}{delta} 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/{gamma}{delta} 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 {gamma}{delta}TCR signaling efficiently diverts thymocytes to the αβ lineage. Immunity 22, 595-606 (2005). [PubMed]

Citation: Signaling Strength Determines T Cell Fate. Sci. STKE 2005, tw197 (2005).



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