Getting the Numbers Right

Abstract

The T cell receptor (TCR)-CD3 complex consists of the antigen-binding TCRαβ dimer in noncovalent association with the δ, ε, γ, and ζ subunits of CD3 (see commentary by Malissen). These subunits contain 10 cytoplasmic immunoreceptor tyrosine-based activation motifs (ITAMs), which, when phosphorylated by tyrosine kinases, become docking sites for downstream signaling molecules, resulting in T cell activation and proliferation and cytokine production. Why each TCR contains 10 ITAM motifs is unclear, so Holst et al . investigated the contributions of individual ITAMs to TCR signaling. They transduced bone marrow cells from CD3-deficient mice with retroviruses that expressed either wild-type or ITAM-mutant CD3 subunits. These cells were transferred into T cell-deficient mice to establish 25 groups of mice with varying combinations of wild-type and ITAM-mutant CD3 subunits. The transferred T cells first traveled to the thymus, where they underwent positive and negative selection. The authors analyzed T cell development and proliferation in the recipient mice. Mice that received less than six ITAMs developed autoimmune diseases, as assessed by immunohistochemistry of affected tissues, whereas those mice with more than six ITAMs did not. There was a positive correlation between the number of ITAMs and T cell proliferation but not cytokine production. Regulatory T cell numbers and function were similar in the different groups of mice, leading the authors to conclude that lack of negative selection of self-reactive CD4 + T cells in the thymus rather than induction of self-reactive cells in the periphery caused autoimmunity. Indeed, lower ITAMs were associated with positive rather than negative selection of self-reactive T cells in other experiments, consistent with the idea that having too few ITAMs results in an insufficiently strong TCR signal to cause negative selection. This study suggests that different numbers of ITAMs are required for different aspects of T cell function, with high numbers required to prevent autoimmunity. J. Holst, H. Wang, K. D. Eder, C. J. Workman, K. L. Boyd, Z. Baquet, H. Singh, K. Forbes, A. Chruscinski, R. Smeyne, N. S. C. van Oers, P. J. Utz, D. A. A. Vignali, Scalable signaling mediated by T cell antigen receptor-CD3 ITAMS ensures effective negative selection and prevents autoimmunity. Nat . Immunol . 9 , 658-666 (2008). [PubMed] B. Malissen, CD3 ITAMs count! Nat . Immunol . 9 , 583-584 (2008). [PubMed]