Interleukin 17 family members in health and disease

The interleukin-17 (IL-17) family consists of six family members (IL-17A–IL-17F) and all the corresponding receptors have been identified recently. This family is mainly involved in the host defense mechanisms against bacteria, fungi and helminth infection by inducing cytokines and chemokines, recruiting neutrophils, inducing anti-microbial proteins and modifying T-helper cell differentiation. IL-17A and some other family cytokines are also involved in the development of psoriasis, psoriatic arthritis and ankylosing spondylitis by inducing inflammatory cytokines and chemokines, and antibodies against IL-17A as well as the receptor IL-17RA are being successfully used for the treatment of these diseases. Involvement in the development of inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis and tumors has also been suggested in animal disease models. In this review, we will briefly review the mechanisms by which IL-17 cytokines are involved in the development of these diseases and discuss possible treatment of inflammatory diseases by targeting IL-17 family members.

The interaction between the immune system and the peripheral sensory nerves in pruritus

Pruritus is a skin-specific sensation that is observed in various skin diseases, especially in inflammatory skin diseases such as atopic dermatitis, and is deeply involved in their pathogenesis. Pruritus also adversely affects patients’ sleep and mental health, placing a heavy burden on daily life. As such, pruritus control is important to the maintenance of health. The mechanism of pruritus has recently been clarified and the discovery of various pruritus mediators, the identification of specific nerves that transmit pruritus and the accumulation of knowledge on pruritus perception have led to a better understanding of all aspects of pruritus generation, transmission and recognition. In the case of pruritus caused by dermatitis, immune cells infiltrating the skin secrete inflammatory cytokines, which also act on peripheral nerves as pruritus mediators and induce an inflammatory response. Interestingly, there has been accumulating evidence that peripheral nerves are also involved in the inflammation via neuropeptides. In this article, we summarize the findings on pruritus mediators secreted by immune cells and the roles of peripheral nerves in pruritus in terms of their interactions with immunity.

T cell-intrinsic and -extrinsic regulation of PD-1 function

Cancer immunotherapies that target PD-1 (programmed cell death 1) aim to destroy tumors by activating tumor-specific T cells that are otherwise inactivated by PD-1. Although these therapies have significantly improved the outcomes of patients with diverse cancer types and have revolutionized cancer treatment, only a limited proportion of patients benefits from the therapies currently. Therefore, there is a continued need to decipher the complex biology of PD-1 to improve therapeutic efficacies as well as to prevent immune-related adverse events. Especially, the spaciotemporal context in which PD-1 functions and the properties of T cells that are restrained by PD-1 are only vaguely understood. We have recently revealed that PD-1 function is strictly restricted at the activation phase of T cell responses by the cis interactions of PD-L1 and CD80 on antigen-presenting cells, which is critical for the induction of optimal T cell responses. We also found that the sensitivity to the effects of PD-1 in T cells is essentially determined by T cell-intrinsic factors. In T cells bearing T cell antigen-receptors (TCRs) with lower affinity to antigenic peptides, PD-1 inhibits the expression of TCR-inducible genes more efficiently; thereby PD-1 preferentially suppresses low-affinity T cells. Thus, PD-1 function is coordinately regulated by various T cell-intrinsic and -extrinsic factors that alter the responsiveness of T cells and the availability of PD-1 ligands. Precise and deeper understanding of the regulatory mechanisms of PD-1 is expected to facilitate the rational development of effective and safe immunotherapies.