The tyrosine phosphatase SHP-1 influences thymocyte selection by setting TCR signaling thresholds

Modulation of the strength of signals from the TCR determines the outcome o f positive and negative selection in thymocyte development. Previous studie s have demonstrated that SHP-1 plays a role in determining signal strength from the TCR. Here, we have taken a genetic approach to test whether SHP-1 plays a role in T cell selection in the thymus. Experiments in which a domi nant negative mutant of SHP-1 was expressed in the BYDP hybridoma cell line confirmed that SHP-1 regulated TCR signaling in a cell-autonomous manner a nd suggested that Lck is one of its targets. To examine the role of SHP-1 i n T cell development, we crossed the ovalbumin-specific DO11.10 TCR transge ne onto the motheaten background, which lacks SHP-1 expression. Analysis of the progeny of these crosses provided evidence that SHP-1. regulates thymo cyte selection: (i) flow cytometric analyses revealed alterations in the pe rcentages of thymocyte subpopulations in the me/me background; (ii) ex vivo deletion experiments demonstrated that me/me:Tg thymocytes undergo negativ e selection at lower concentrations of OVA peptide compared to +/+:Tg thymo cytes; and (iii) ex vivo proliferation analyses indicated that me/me:Tg thy mocytes were hyper-sensitive to stimulation by the specific OVA peptide. Ou r observation that the absence of SHP-1 leads to altered selection of TCR t ransgenic thymocytes demonstrates that SHP-1 regulates the strength of TOP- mediated signals in vivo and, in turn, helps to set the threshold for thymo cyte selection.