Editors' ChoiceImmunology

Cbl-b Controls T Cell Receptor Aggregation

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Science's STKE  31 Oct 2000:
Vol. 2000, Issue 56, pp. tw6
DOI: 10.1126/stke.2000.56.tw6

T cell activation and proliferation require at least two events at the plasma membrane including the activation of both the T cell antigen receptor (TCR)-CD3 complex and a costimulatory protein, CD28. Immune synapse formation (i.e., aggregation of multiple clusters of antigen receptors) is CD28-dependent. Uncontrolled immune synapse formation is thought to contribute to some instances of autoimmunity. Thus, uncovering the mechanisms of immune synapse formation might lead to better designed treatments for patients with autoimmune syndromes. Mice deficient in Cbl-b, a protein thought to have a role in ubiquitin ligation, exhibit B and T lymphocytic hyperproliferation and autoimmunity. Krawczyk et al. have now identified Cbl-b as a negative regulator of receptor aggregation. T cells from Cbl-b-deficient mice had normal TCR-CD3- and CD28-dependent activation of several mitogen-activated protein kinase (MAPK) pathways and Ca2+ mobilization; however, Cbl-b deficiency resulted in the uncoupling of CD28-dependency in receptor clustering and filopodia formation. Similarly, in Cbl-b-deficient T cells, CD3 cross-linking alone was sufficient for the activation of several cytoplasmic TCR signaling proteins. T cells deficient in Vav1, a guanine nucleotide exchange protein for Cdc42, exhibit impaired proliferation and receptor clustering; however, cbl-b mutants restored proliferation (and subsequent hyperproliferation and autoimmunity), and receptor clustering to vav1-/- T cells. Thus, because both Cbl-b- and Cbl-b/Vav1-deficient mice develop autoimmunity, the authors suggest that autoimmunity may arise from those pathways that control receptor aggregation and involve Cbl-b.

Krawczyk, C., Bachmaier, K., Sasaki, T., Jones, R.G., Snapper, S.B., Bouchard, D., Kozieradzki, I., Ohashi, P.S., Alt, F.W., and Penninger, J.M. (2000) Cbl-b is a negative regulator of receptor clustering and raft aggregation in T cells. Immunity 13: 463-473. [Online Journal]

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