ROLE OF THE PRE-T CELL RECEPTOR IN LINEAGE COMMITMENT

Dana-Farber Cancer Institute, Boston MA

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Abstract

The development of alphabeta T cells in the thymus is controlled at the first checkpoint by the pre-T cell receptor (TCR), that consists of the TCRbeta chain covalently paired with the pre- TCRalpha (pTalpha) chain, in association with the signal transducing CD3 molecules. In pTalpha deficient mice development of the alphabeta lineage of T cells is severely compromised, while gammadelta T cells are numerically elevated. Nevertheless, on the basis of the analysis of Vbeta rearrangement in gammadelta T cells it has been argued that, since up to 70 percent of such rearrangements appear to be in frame, the pre-TCR has a role in TCRbeta selection of gammadelta T cells. We have re-analyzed Vbeta rearrangement in gammadelta T cells from normal and pTalpha-deficient mice by single cell polymerase chain reaction (PCR), and found that Vbeta-rearrangement proceeds further in gammadelta T cells derived from pTalpha-/- than those derived from normal mice. Furthermore, we observed selection against inframe rearrangement in the latter but not the former cells. On the basis of these results we propose to study whether the pre- TCR on the one hand and the gammadelta TCR on the other hand generate distinct signals that result in different lineage committments. To this end we will construct pro-Tcell lines as well as mice that express inducible TCRbeta TCRgamma and delta transgenes, so that lineage commitment and putative distinct signals transmitted by the different receptors, as well as the consequences of signal transduction, can be analyzed in cells that have just expressed one or the other receptor.