In addition to their role in binding antigen, antibodies can regulate immune responses through interacting with Fc receptors (FcRs). In recent years, significant progress has been made in understanding the mechanisms that regulate the activity of IgG antibodies in vivo. In this Review, we discuss recent studies addressing the multifaceted roles of FcRs for IgG (FcgammaRs) in the immune system and how this knowledge could be translated into novel therapeutic strategies to treat human autoimmune, infectious or malignant diseases.

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Fcγ receptors as regulators of immune responses

Dendritic cells (DCs) orchestrate a repertoire of immune responses that bring about resistance to infection and silencing or tolerance to self. In the settings of infection and cancer, microbes and tumours can exploit DCs to evade immunity, but DCs also can generate resistance, a capacity that is readily enhanced with DC-targeted vaccines. During allergy, autoimmunity and transplant rejection, DCs instigate unwanted responses that cause disease, but, again, DCs can be harnessed to silence these conditions with novel therapies. Here we present some medical implications of DC biology that account for illness and provide opportunities for prevention and therapy.

Taking dendritic cells into medicine

Dendritic cells (DCs) form a remarkable cellular network that shapes adaptive immune responses according to peripheral cues. After four decades of research, we now know that DCs arise from a hematopoietic lineage distinct from other leukocytes, establishing the DC system as a unique hematopoietic branch. Recent work has also established that tissue DCs consist of developmentally and functionally distinct subsets that differentially regulate T lymphocyte function. This review discusses major advances in our understanding of the regulation of DC lineage commitment, differentiation, diversification, and function in situ.

The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting.

Cancer immunotherapy attempts to harness the power and specificity of the immune system to treat tumours. The molecular identification of human cancer-specific antigens has allowed the development of antigen-specific immunotherapy. In one approach, autologous antigen-specific T cells are expanded ex vivo and then re-infused into patients. Another approach is through vaccination; that is, the provision of an antigen together with an adjuvant to elicit therapeutic T cells in vivo. Owing to their properties, dendritic cells (DCs) are often called 'nature's adjuvants' and thus have become the natural agents for antigen delivery. After four decades of research, it is now clear that DCs are at the centre of the immune system owing to their ability to control both immune tolerance and immunity. Thus, DCs are an essential target in efforts to generate therapeutic immunity against cancer.

Cancer immunotherapy via dendritic cells

Although in vitro observations suggest that cross-presentation of antigens is mediated primarily by CD8α+ dendritic cells, in vivo analysis has been hampered by the lack of systems that selectively eliminate this cell lineage. We show that deletion of the transcription factor Batf3 ablated development of CD8α+ dendritic cells, allowing us to examine their role in immunity in vivo. Dendritic cells from Batf3–/– mice were defective in cross-presentation, and Batf3–/– mice lacked virus-specific CD8+ T cell responses to West Nile virus. Importantly, rejection of highly immunogenic syngeneic tumors was impaired in Batf3–/– mice. These results suggest an important role for CD8α+ dendritic cells and cross-presentation in responses to viruses and in tumor rejection.

https://science.sciencemag.org/content/sci/322/5904/1097.full.pdf

Batf3 Deficiency Reveals a Critical Role for CD8α+ Dendritic Cells in Cytotoxic T Cell Immunity

Dendritic cells (DCs) process and present self and foreign antigens to induce tolerance or immunity. In vitro models suggest that induction of immunity is controlled by regulating the presentation of antigen, but little is known about how DCs control antigen presentation in vivo. To examine antigen processing and presentation in vivo, we specifically targeted antigens to two major subsets of DCs by using chimeric monoclonal antibodies. Unlike CD8+ DCs that express the cell surface protein CD205, CD8- DCs, which are positive for the 33D1 antigen, are specialized for presentation on major histocompatibility complex (MHC) class II. This difference in antigen processing is intrinsic to the DC subsets and is associated with increased expression of proteins involved in MHC processing.

https://science.sciencemag.org/content/sci/315/5808/107.full.pdf

Veit R. Buchholz

Papers

Differential antigen processing by dendritic cell subsets in vivo