ITK gain of function genetic variation drives human autoimmunity and is responsive to T cell inhibition

IL-2 inducible T cell Kinase (ITK) is critical to T cell receptor signalling and responses and loss of function ITK genetic variants are associated with impaired immune responses. Here, we report a novel, heterozygous missense gain of function (GoF) variant, ITKE42K, in a family with complex autoimmune disease associated with exhausted CD8+ and CD4+ memory T cells. We show the variant lysine at residue 42 of the pleckstrin homology domain of ITK promotes stable interactions with calcium sensor calmodulin and membrane bound phosphatidylinositol phosphates. This results in sustained T cell signalling with increased calcium flux in human and murine T cells and augmented nuclear factor of activated T cell activity. CRISPR generated ItkE42K mice have enhanced formation of pro-inflammatory T helper cells, Th1, Th2 and Th17 cells and as a result, ItkE42K mice have increased development of anti-collagen autoantibodies. Itk E42K also increases IL-2 mediated T cell survival and expands pathogenic double negative T cells and causes fatal lymphoma in FasLpr mice. We identify two additional GoF variants, ITK N114H and ITK T504S, in 7 unrelated pedigrees with autoimmunity. Targeting increased nuclear factor of activated T cell with tacrolimus normalised ITK signalling in T cells resulting in successful resolution of the proband's disease.