Itk (inducible T cell kinase) is a member of the Tec kinase family of nonreceptor protein tyrosine kinases that are expressed in T cells, NK cells, and mast cells. Defects in Itk protein lead to impaired T cell activation and effector function. Although mice lacking Itk are impaired in their ability to generate protective Th1 and Th2 responses in vivo, LCMV clearance requiring CD8+ T cells appear to be intact. Contact sensitivity (CS) is a type IV hypersensitivity reaction resulting from secondary skin exposure to a reactive hapten. Murine models of CS using chemical haptens such as DNFB are shown to be predominantly CD8+ T cell mediated with CD4+ T cells acting as modulators. Recently, data from CS models using FITC suggest a dominant role of Th2-type CD4+ T cells. The purpose of our studies was to determine whether Itk plays a role in the development of contact sensitivity responses to FITC or DNFB using Itk knockout mice. Indeed mice lacking Itk have significantly reduced ear swelling and leukocyte infiltration following FITC ear challenge compared to WT mice, which correlates with the lack of FITC-specific cytokine secretion from primed Itk KO LNC in vitro. In contrast, Itk−/− mice were able to generate ear swelling responses comparable to WT mice following DNFB challenge. Together, these data further support the effector role of CD4+ T cells in FITC-CS and the inability of Itk−/− mice to generate effective Th2 responses in vivo.

During the development of multiple sclerosis the destruction of the myelin sheath surrounding the neurites is accompanied by citrullination of several central nervous system (CNS) proteins, including myelin basic protein and glial fibrillary acidic protein. In experimental autoimmune encephalomyelitis (EAE), a disease induced in animals by immunization with proteins or peptides from the CNS, the animals develop symptoms similar to multiple sclerosis (MS). The increased levels of citrullinated CNS proteins associated with MS are also observed during the development of EAE. To study the role of CNS protein citrullination in EAE development, we induced EAE with a peptide derived from myelin oligodendrocyte glycoprotein (MOG(35-55)) in mice lacking the peptidylarginine deiminase 2 (PAD2) protein, because this enzyme was the most likely candidate to be involved in catalyzing CNS protein citrullination in the diseased state. Even though the PAD2 knockout mice displayed a dramatic reduction in the amount of citrullination present in the CNS, indicating that PAD2 is indeed responsible for the majority of detectable citrullination observed in EAE, the development of EAE was not impaired by genetic deletion of PAD2, suggesting that PAD2 catalyzed citrullination is not essential to the development of EAE.