Beyond cDC1: Emerging Roles of DC Crosstalk in Cancer Immunity

Dendritic cells (DCs) efficiently process and present antigens to T cells, and by integrating environmental signals, link innate and adaptive immunity. DCs also control the balance between tolerance and immunity, and are required for T-cell mediated anti-tumor immunity. One subset of classical DCs, cDC1, are particularly important for eliciting CD8 T cells that can kill tumor cells. cDC1s are superior in antigen cross-presentation, a process of presenting exogenous antigens on MHC class I to activate CD8+ T cells. Tumor-associated cDC1s can transport tumor antigen to the draining lymph node and cross-present tumor antigens, resulting in priming and activation of cytotoxic T cells. Although cross-presenting cDC1s are critical for eliciting anti-tumor T cell responses, the role and importance of other DC subsets in anti-tumor immunity is not as well-characterized. Recent literature in other contexts suggests that critical crosstalk between DC subsets can significantly alter biological outcomes, and these DC interactions likely also contribute significantly to tumor-specific immune responses. Therefore, antigen presentation by cDC1s may be necessary but not sufficient for maximal immune responses against cancer. Here, we discuss recent advances in the understanding of DC subset interactions to maximize anti-tumor immunity, and propose that such interactions should be considered for the development of better DC-targeted immunotherapies

The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells

Interleukin (IL) 6 is a proinflammtory cytokine produced by antigen-presenting cells and nonhematopoietic cells in response to external stimuli. It was initially identified as a B cell growth factor and inducer of plasma cell differentiation in vitro and plays an important role in antibody production and class switching in vivo. However, it is not clear whether IL-6 directly affects B cells or acts through other mechanisms. We show that IL-6 is sufficient and necessary to induce IL-21 production by naive and memory CD4+ T cells upon T cell receptor stimulation. IL-21 production by CD4+ T cells is required for IL-6 to promote B cell antibody production in vitro. Moreover, administration of IL-6 with inactive influenza virus enhances virus-specific antibody production, and importantly, this effect is dependent on IL-21. Thus, IL-6 promotes antibody production by promoting the B cell helper capabilities of CD4+ T cells through increased IL-21 production. IL-6 could therefore be a potential coadjuvant to enhance humoral immunity

Sex-Specific Control of Central Nervous System Autoimmunity by p38 Mitogen-Activated Protein Kinase Signaling in Myeloid Cells

OBJECTIVE: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), characterized by a global increasing incidence driven by relapsing-remitting disease in females. p38 MAP kinase (MAPK) has been described as a key regulator of inflammatory responses in autoimmunity, but its role in the sexual dimorphism in MS or MS models remains unexplored. METHODS: Toward this end, we used experimental autoimmune encephalomyelitis (EAE), the principal animal model of MS, combined with pharmacologic and genetic inhibition of p38 MAPK activity and transcriptomic analyses. RESULTS: Pharmacologic inhibition of p38 MAPK selectively ameliorated EAE in female mice. Conditional deletion studies demonstrated that p38α signaling in macrophages/myeloid cells, but not T cells or dendritic cells, recapitulated this sexual dimorphism. Analysis of CNS inflammatory infiltrates showed that female, but not male mice lacking p38α in myeloid cells exhibited reduced immune cell activation compared with controls, while peripheral T cell priming was unaffected in both sexes. Transcriptomic analyses of myeloid cells revealed differences in p38α-controlled transcripts comprising female- and male-specific gene modules, with greater p38α dependence of pro-inflammatory gene expression in females. INTERPRETATION: Our findings demonstrate a key role for p38α in myeloid cells in CNS autoimmunity and uncover important molecular mechanisms underlying sex differences in disease pathogenesis. Taken together, our results suggest that the p38 MAPK signaling pathway represents a novel target for much needed disease modifying therapies for MS

Activation of p38 MAPK in CD4 T cells controls IL-17 production and autoimmune encephalomyelitis

Although several transcription factors have been shown to be critical for the induction and maintenance of IL-17 expression by CD4 Th cells, less is known about the role of nontranscriptional mechanisms. Here we show that the p38 MAPK signaling pathway is essential for in vitro and in vivo IL-17 production by regulating IL-17 synthesis in CD4 T cells through the activation of the eukaryotic translation initiation factor 4E/MAPK-interacting kinase (eIF-4E/MNK) pathway. We also show that p38 MAPK activation is required for the development and progression of both chronic and relapsing-remitting forms of experimental allergic encephalomyelitis (EAE), the principal autoimmune model of multiple sclerosis. Furthermore, we show that regulation of p38 MAPK activity specifically in T cells is sufficient to modulate EAE severity. Thus, mechanisms other than the regulation of gene expression also contribute to Th17 cell effector functions and, potentially, to the pathogenesis of other Th17 cell-mediated diseases