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Role of the Multiple T Cell Receptor (TCR)- Chain Signaling Motifs in Selection of the T Cell Repertoire

Elizabeth W. Shores^*, Tom Tran^*, Alexander Grinberg, Connie L. Sommers, Howard Shen, and Paul E. Love

From the ^* Division of Hematologic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892; and the Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

Immature thymocytes undergo a selection process within the thymus based on their T cell antigen receptor (TCR) specificity that results either in their maturation into functionally competent, self-MHC–restricted T cells (positive selection) or their deletion (negative selection). The outcome of thymocyte selection is thought to be controlled by signals transduced by the TCR that vary in relation to the avidity of the TCR–ligand interaction. The TCR is composed of four distinct signal transducing subunits (CD3-, -, -, and ) that contain either one (CD3-, -, -) or three (-) signaling motifs (ITAMs) within their intracytoplasmic domains. A possible function for multiple TCR ITAMs could be to amplify signals generated by the TCR during selection. To determine the importance of the multiple TCR- chain ITAMs in thymocyte selection, transgenes encoding /βTCRs with known specificity were bred into mice in which chains lacking one or more ITAMs had been genetically substituted for endogenous . A direct relationship was observed between the number of chain ITAMs within the TCR complex and the efficiency of both positive and negative selection. These results reveal a role for multiple TCR ITAMs in thymocyte selection and identify a function for TCR signal amplification in formation of the T cell repertoire.

¹Abbreviations used in this paper: DP, double positive; FCM, flow cytometry; ITAM, immunoreceptor tyrosine-based activation motif; SEB, Staphylococcus enterotoxin B; SP, single positive.

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