Immunity to Pathogens Taught by Specialized Human Dendritic Cell Subsets

Jens Geginat,Paola Larghi,Sergio Abrignani,Giulia Nizzoli,Moira Paroni,Steve Pascolo,Stefano Maglie

doi:10.3389/fimmu.2015.00527

Abstract

Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) that have a key role in immune responses because they bridge the innate and adaptive arms of the immune system. They mature upon recognition of pathogens and upregulate MHC molecules and costimulatory receptors to activate antigen-specific CD4+ and CD8+ T cells. It is now well established that DCs are not a homogeneous population but are composed of different subsets with specialized functions in immune responses to specific pathogens. Upon viral infections, plasmacytoid DCs (pDCs) rapidly produce large amounts of IFN-α, which has potent antiviral functions and activates several other immune cells. However, pDCs are not particularly potent APCs and induce the tolerogenic cytokine IL-10 in CD4+ T cells. In contrast, myeloid DCs (mDCs) are very potent APCs and possess the unique capacity to prime naive T cells and consequently to initiate a primary adaptive immune response. Different subsets of mDCs with specialized functions have been identified. In mice, CD8α+ mDCs capture antigenic material from necrotic cells, secrete high levels of IL-12, and prime Th1 and cytotoxic T-cell responses to control intracellular pathogens. Conversely, CD8α− mDCs preferentially prime CD4+ T cells and promote Th2 or Th17 differentiation. BDCA-3+ mDC2 are the human homologue of CD8α+ mDCs, since they share the expression of several key molecules, the capacity to cross-present antigens to CD8+ T-cells and to produce IFN-λ. However, although several features of the DC network are conserved between humans and mice, the expression of several toll-like receptors as well as the production of cytokines that regulate T-cell differentiation are different. Intriguingly, recent data suggest specific roles for human DC subsets in immune responses against individual pathogens. The biology of human DC subsets holds the promise to be exploitable in translational medicine, in particular for the development of vaccines against persistent infections or cancer.

Highlights

Human beings are constantly exposed to a myriad of pathogens, including bacteria, fungi, and viruses
The adaptive immune system is composed of B cells that produce specific antibodies, CD8+ T cells that can kill pathogen-infected cells, and CD4+ T cells that produce effector cytokines and coordinate the immune response
CD8+ T cells recognize peptides presented by MHC class-I molecules that are ubiquitously expressed, whereas CD4+ T cells are activated by peptide-MHC class-II complexes, which are largely restricted to antigen-presenting cells (APCs)

Summary

INTRODUCTION

Human beings are constantly exposed to a myriad of pathogens, including bacteria, fungi, and viruses. IL-4 is the critical cytokine that induces this response [16], but IL-4 is normally not produced by DC [17, 18] These different effector responses have to be controlled by specialized regulatory T cells, in particular by IL-10-producing T cells (“Tr1 cells”), which are generated from effector cells and are important to avoid excessive tissue damage by adaptive immune responses [19,20,21,22]. The presentation of peptides derived from exogenous proteins on MHC class-I, a process called cross-presentation [31, 32], is a largely unique feature of DCs and is important to activate CD8+ T cells in viral infections. Antigen presentation by B cells appears to be important for the activation of antigen-experienced T cells rather than for naive T-cell priming

PATTERNS INDUCE DC MATURATION

SUBSETS IN HUMANS AND MICE

SPECIFIC ROLES OF HUMAN DC SUBSETS IN RESPONSES TO INDIVIDUAL PATHOGENS

IMMUNE RESPONSES

CONCLUSION AND PERSPECTIVE