Yanyan Wang, Gonghua Huang, Caryn Cloer, Hongbo Chi, PhD St. Jude Children’s Research Hospital

Bridging Innate Immunity and Adaptive Immunity to Program Inflammatory T-Cell Development

Antigen-presenting dendritic cells serve as a bridge between the two major categories of immune response, innate immunity and adaptive immunity. During the innate immune response, dendritic cells recognize the microbial pathogen. The cells then activate a signaling cascade that triggers the activation and differentiation of naïve T cells, thereby inducing the adaptive immune response.

CD4+ T cells are central regulators of adaptive immune responses. For more than 20 years, researchers have appreciated that naïve CD4+ T cells can differentiate into distinct lineages to attain specialized properties and effector functions. Of the initially identified helper T-cell subsets, TH1 cells are characterized by high production of IFN-γ and are necessary to clear intracellular pathogens. TH2 cells produce the signature cytokine interleukin-4 (IL-4) and effectively control infection with helminths, a type of parasitic worms.

A newly discovered subset of IL-17–producing T (TH17) cells plays a key role in the immune defense against fungi and extracellular bacteria. However, TH17 cells also contribute to the pathogenesis of many autoimmune conditions such as multiple sclerosis, an inflammatory disease of the central nervous system in which the myelin sheath of nerve cells in the brain and spinal cord breaks down. Whether TH17-cell differentiation is shaped by extrinsic pathways such as those influenced by the innate immune response remains unclear.

In a recent report published in Nature Immunology, Hongbo Chi, PhD (Immunology), and his group explored the roles of p38α MAPK signaling in the pathogenesis of autoimmune disease. Using the experimental autoimmune encephalomyelitis (EAE) murine model of multiple sclerosis, the investigators showed that p38α-deficient dendritic cells, but not macrophages or T cells, protect mice from autoimmune pathogenesis. Such protection was associated with the impaired development of pathogenic TH17 cells but not TH1 or TH2 cells.

The activity of p38α was dynamically regulated by diverse innate signals in dendritic cells. Once activated, p38α orchestrated the expression of cytokines and costimulatory molecules (i.e., IL-6, IL-27, and CD86) in dendritic cells to promote TH17-cell differentiation. This study established p38α as one of the major signals needed to program dendritic cell–T-cell crosstalk for autoimmune inflammation.

In efforts to develop new anti-inflammatory drugs, p38α is by far the most extensively investigated protein kinase target explored by the pharmaceutical industry, but severe side effects have prevented the clinical advancement of p38α inhibitors. The activity of p38α is conserved between mouse and human dendritic cells, and acute inhibition of p38α in dendritic cells effectively curtails TH17-cell responses and inflammation. Therefore, selectively targeting p38α activity in dendritic cells is a promising strategy for treating multiple sclerosis and other autoimmune diseases mediated by TH17 cells.