From periphery to center stage: 50 years of advancements in innate immunity

Abstract

Over the past 50 years in the field of immunology, something of a Copernican revolution has happened. For a long time, immunologists were mainly concerned with what is termed adaptive immunity, which involves the exquisitely specific activities of lymphocytes. But the other arm of immunity, so-called "innate immunity," had been neglected. To celebrate Cell's 50^th anniversary, we have put together a review of the processes and components of innate immunity and trace the seminal contributions leading to the modern state of this field. Innate immunity has joined adaptive immunity in the center of interest for all those who study the body's defenses, as well as homeostasis and pathology. We are now entering the era where therapeutic targeting of innate immune receptors and downstream signals hold substantial promise for infectious and inflammatory diseases and cancer.

Fig. 1:. Key discoveries in innate immunity over the past 50 years.

Here we outline the key discoveries in innate immunity through the decades. It begins with the discovery of dendritic cells in 1973 and moves through the key events of cloning cytokines (TNF) identification of the receptors (TLRs, inflammasome, cGAS) and mechanisms of action to the final development of drugs targeting the pathways (NLRP inhibitors).

Fig. 2:. Molecular patterns induce a variety of cellular responses via distinct sensing pathways.

TLR signaling: plasma membrane bound or endosomally localized TLRs signal through adaptors and kinases situated in the cytosol to drive inflammatory cytokines and type 1 interferons (IFN) responses. Inflammasome: The inflammasome is a multiprotein complex formed in the cytosol in responses to microbial ligands or host danger signals. Activation leads to caspase 1 activity, cleavage, and release of IL1b or IL18. Nucleic Acid Sensing. DNA is recognized by cGAS within the cytosol, leading to the production of the second messenger cGAMP, which signals through STING to induce type 1 IFNs. RNA is sensed by RIG-1 or MDA5 to induced type I IFNs Noncoding Regulation. Many families of noncoding RNAs including lncRNAs, tRNA fragments, miRNAs and circRNAs have emerged as key regulators of biological including transcription, splicing and translation which can impact immunity.