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CD3 ITAMs count!

Nature Immunology volume 9, pages 583–584 (2008)Cite this article

The T cell receptor (TCR) is functionally coupled to a constellation of ten immunoreceptor tyrosine–based activation motifs (ITAMs). A new study suggests that this large number of ITAMs is mandatory for preventing autoimmunity.

Immunodeficient mice were reconstituted with hematopoietic stem cells that were isolated from mice deprived of all CD3 subunits and that were infected with multicistronic retroviral vectors encoding combinations of CD3 subunits containing functional or inactivated ITAMs. Analysis of 25 groups of these 'retrogenic' mice expressing graded numbers of functional CD3 ITAMs showed that almost all mice with fewer than seven functional ITAMs developed fulminant multiorgan inflammatory diseases triggered by CD4+ T cells. The sporadic presence of autoantibodies 6 weeks after bone marrow transfer, the mild in vitro CD4+ T cell proliferation noted in response to autologous APCs and the presence of functionally competent Foxp3+ regulatory T (Treg) cells led Holst et al.1 to conclude that in mice with fewer than seven functional ITAMS, a breakdown in central rather than peripheral tolerance triggered the generation of interferon-γ-producing autoreactive CD4+ T cells. These findings are surprising because in previous studies based on conventional transgenesis, CD3ζ-deficient mice complemented with ITAM-less CD3ζ subunits did not develop any signs of inflammation despite having six or fewer functional ITAMs in their TCRs2,3. Whether the expression of lower amounts of TCR on the surface of T cells from retrogenic mice accounts for this discrepancy remains to be determined. However, it is important to emphasize that thymi and spleens of retrogenic mice reconstituted with wild-type CD3 chains contained only one-tenth as many T cells as corresponding organs from unmanipulated mice, suggesting that lymphopenia might contribute in part to the phenotype observed in some retrogenic mice.

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Figure 1: TCR-CD3 complexes on αβ T cells contain a single antigen-binding TCR heterodimer that assembles with single CD3γε, CD3δε and CD3ζζ pairs.

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Authors and Affiliations

  1. Bernard Malissen is at the Centre d'Immunologie de Marseille–Luminy, Université de la Méditerrannée, INSERM U631, CNRS UMR6102, 13288 Marseille Cedex 9, France. bernardm@ciml.univ-mrs.fr,

    Bernard Malissen

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Malissen, B. CD3 ITAMs count!. Nat Immunol 9, 583–584 (2008). https://doi.org/10.1038/ni0608-583

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