One Tyrosine Short

LAT is an intracellular adaptor protein that becomes phosphorylated on multiple tyrosine residues after T cell receptor activation. Agaudo et al. and Sommers et al. report that a single tyrosine residue in LAT, which couples to the downstream signaling molecule phospholipase C-γ1, plays a crucial role in maintaining T cell homeostasis, regulating both early and late T cell development and differentiation. Replacement of endogenous LAT in mice with a form in which Tyr136 was mutated to Phe caused a partial block in early T cell development. However, over time, the mice developed a fatal lymphoproliferative disorder featuring an overabundance of a particular Th2-type cell. One consequence of this paradoxical phenotype was an autoimmune response. The analyses suggest that, although a single LAT residue may have a positive function during early T cell development, it may negatively regulate signaling pathways later on during T cell selection and differentiation of Th2 effector cells. E. Aguado, S. Richelme, S. Nuñez-Cruz, A. Miazek, A.-M. Mura, M. Richelme, X.-J. Guo, D. Sainty, H.-T. He, B. Malissen, M. Malissen, Induction of T helper type 2 immunity by a point mutation in the LAT adaptor. Science 296, 2036-2040 (2002). [Abstract] [Full Text] C. L. Sommers, C.-S. Park, J. Lee, C. Feng, C. L. Fuller, A. Grinberg, J. A. Hildebrand, E. Lacaná, R. K. Menon, E. W. Shores, L. E. Samelson, P. E. Love, A LAT mutation that inhibits T cell development yet induces lymphoproliferation. Science 296, 2040-2043 (2002). [Abstract] [Full Text]