Linker for activation of T cells (LAT) is a transmembrane adaptor protein playing a key role in the development, activation and maintenance of peripheral homeostasis of T cells. In this study we identified a functional isoform of LAT. It originates from an intron 6 retention event generating an in-frame splice variant of LAT mRNA denoted as LAT i6 . Comparison of LAT i6 expression in peripheral blood leukocytes of human and several other mammalian species revealed that it varied from being

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... ally absent in the mouse to being predominant in the cow. Analysis of LAT isoform frequency expressed from minigene splicing reporters carrying loss-or gain-of-function point mutations within intronic polyguanine sequences showed that these elements are critical for controlling the intron 6 removal. The protein product of LAT i6 isoform (LAT i6 ) ectopically expressed in LAT-deficient JCam 2.5 cell line localized correctly to subcellular compartments and supported T-cell receptor signaling but differed from the canonical LAT protein by displaying a shorter half-life and mediating an increased interleukin-2 secretion upon prolonged CD3/CD28 crosslinking. Altogether, our data suggest that the appearance of LAT i6 isoform is an evolutionary innovation that may contribute to a more efficient proofreading control of effector T-cell response.