Phagocytosis of Particulate Antigens – All Roads Lead to Calcineurin/NFAT Signaling Pathway

Abstract

Antigen-presenting cells (APC) possess multiple cell surface receptors that recognize common microbe-associated antigens as well as immune complexes and inert particles. Upon encountering such antigens these receptors must cooperate to achieve phagocytosis and trigger signaling cascades that initiate the innate immune response. While the stimuli initiating these signaling cascades are diverse, recent data have revealed that their effects in APC and particularly in dendritic cells (DC), all have something in common: downstream activation of nuclear factor of activated T cells (NFAT). NFAT is a family of transcription factors that has emerged as a key mediator of the initiation of immune responses by APCs, and specifically of IL-2 production by DC as reviewed (1). Intriguingly NFAT activation now seems to be the shared endpoint of several signaling pathways that all begin with uptake of particulate antigens. Notably, the NFAT family members appeared at the origin of vertebrates whereas nearly all the other signaling pathways, including NFκB pathway, are very ancient and present in all invertebrate’s species. NFAT signaling plays essential roles in vertebrate organogenesis and development but also in the formation of adaptive immunity. In addition, G. R. Crabtree has suggested that “NFAT may have contributed to the evolutionary adaptation of innate immunity: e.g., minimize the costs of inflammation by collaboration with adaptive immunity” (2). It is likely that the ability of DC to link innate with adaptive immunity might be the result of DC’s ability to couple phagocytic functions to NFAT activation, leading to extensive gene reprograming. This is the latest in a series of new hypothesis to better understand of the true complexity of the process of pathogen sensing, uptake, and response in APC and in particular in DC. But as is so often the case, with new hypotheses and knowledge has come new questions: how can such diverse stimuli all converge on similar pathways of immune activation? How do APCs integrate signaling from multiple immune uptake receptors? And how can we explain the difference in APC responses to soluble and particulate antigens? In this article we will review the recent steps forward in our understanding of the intricate cross-talk between pathways of phagocytosis and immune signaling in APC, and the evidence that NFAT activation is a unique hallmark of this process.