Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT.

J Exp Med          online article

In BIOSS we study the signalling mechanisms leading to T cell activation. Loss-of-function studies are mostly carried out in mice. Since mice are not humans, it is always informative to also analyse human loss-of-function muntants. The adapter protein linker for activation of T cells (LAT) is a critical adaptor protein in T cell activation. In this collaborative study, we describe the first human family with defective LAT signaling caused by a homozygous mutation in the LAT gene, leading to a premature stop codon deleting most of the cytoplasmic tail of LAT, including the critical tyrosine residues for signalling. The patients presented from early childhood with combined immunodeficiency and autoimmune diseases. In contrast to the mouse counterparts, T cell numbers were reduced in the LAT-mutated patients. Despite the reported nonredundant role of LAT in Ca²⁺ mobilization, residual T cells were able to induce Ca²⁺ influx and NFκB signaling, whereas ERK signaling was completely abolished. This is the first report of a LAT-related disease in humans, thus contributing to expand the BIOSS findings of signalling processes from mouse to human.