The pathology of psoriasis strongly depends on IL-17A. Monoclonal antibodies blocking either the cytokine or its receptor are among the most efficient treatments for psoriatic patients. Keratinocytes can be activated upon exposure to IL-17A and tumor necrosis factor-a and secrete secondary cytokines and chemokines in the inflamed skin. In psoriasis and its imiquimod-induced mouse model, a strong skin infiltration of neutrophils and inflammatory monocytes can be observed. However, to date, it is not clear how exactly those cellular populations are attracted to the skin and how they contribute to the pathogenesis of the disease. To define the crucial cell type responding to IL-17 and initiating the downstream pathology in psoriasis-like dermatitis, we used mice specifically lacking the IL-17 receptor (IL-17RA) in different cell types. Deletion of IL-17RA in T cells or myeloid had no impact on disease development. Only deletion of this receptor in keratinocytes reflected the full-body deletion of IL-17RA, resulting in strongly reduced dermatitis development. Imiquimod treatment of those IL-17 signalingedeficient mice maintained high monocytic infiltration but failed to attract neutrophils into the skin. We conclude that keratinocytes are a critical cellular target for IL-17Aemediated neutrophil attraction and psoriasis development.

Multiple lines of evidence suggest that CD8 T cells contribute to the pathogenesis of multiple sclerosis (MS). However, the sources and involvement of cytokines such as IL-15 in activating these cells is still unresolved. To investigate the role of IL-15 in enhancing the activation of CD8 T cells in the context of MS, we determined cell types expressing the bioactive surface IL-15 in the peripheral blood of patients and evaluated the impact of this cytokine on CD8 T cell cytotoxicity and migration. Flow cytometric analysis showed a significantly greater proportion of B cells and monocytes from MS patients expressing IL-15 relative to controls. We established that CD40L activation of B cells from healthy donors increased their IL-15 levels, reaching those of MS patients. We also demonstrated an enhanced cytotoxic profile in CD8 T cells from MS patients upon stimulation with IL-15. Furthermore, we showed that IL-15 expressed by B cells and monocytes is sufficient and functional, enhancing granzyme B production by CD8 T cells upon coculture. Exposure of CD8 T cells to this cytokine enhanced their ability to kill glial cells as well as to migrate across an in vitro inflamed human blood–brain barrier. The elevated levels of IL-15 in patients relative to controls, the greater susceptibility of CD8 T cells from patients to IL-15, in addition to the enhanced cytotoxic responses by IL-15–exposed CD8 T cells, stresses the potential of therapeutic strategies to reduce peripheral sources of IL-15 in MS.

Reversible protein phosphorylation plays a pivotal role in intercellular communication. Together with protein tyrosine kinases, protein tyrosine phosphatases (PTPs) are involved in the regulation of key cellular processes by controlling the phosphorylation levels of diverse effectors. Among PTPs, receptor-like protein tyrosine phosphatases (RPTPs) are involved in important developmental processes, particularly in the formation of the nervous system. Until recently, few ligands had been identified for RPTPs, making it difficult to grasp the effects these receptors have on cellular processes as well as the mechanisms through which their functions are mediated. However, several potential RPTP ligands have now been identified to provide us with unparalleled insights into RPTP function. In this review, we will focus on the nature and biological outcomes of these extracellular interactions between RPTPs and their associated ligands.

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Highlights d A20-deficient microglia acquire an inflammatory signature seen in viral infections d CD8 + T cells infiltrate the CNS when microglia lack A20 d Infiltrating CD8 + T cells are responsible for phenotypic changes in microglia and neurons d Cortical neurons are hyperactive and have an increased number of synaptic terminals