The immune system is under control of the circadian clock. Many of the circadian rhythms observed in the immune system originate in direct interactions between components of the circadian clock and components of the immune system. The main means of circadian control over the immune system is by direct control of circadian clock proteins acting as transcription factors driving the expression or repression of immune genes. A second circadian control of immunity lies in the acetylation or methylation of histones to regulate gene transcription or inflammatory proteins. Furthermore, circadian clock proteins can engage in direct physical interactions with components of key inflammatory pathways such as members of the NFkB protein family. This regulation is transcription independent and allows the immune system to also reciprocally exert control over circadian clock function. Thus, the molecular interactions between the circadian clock and the immune system are manifold. We highlight and discuss here the recent findings with respect to the molecular mechanisms that control time-of-day-dependent immunity. This review provides a structured overview focusing on the key circadian clock proteins and discusses their reciprocal interactions with the immune system.

Introduction

Virtually every organism continuously faces daily and seasonal environmental changes. Organisms anticipate and respond to these changes by tuning their behavior, metabolism, and also their immune system accordingly. Daily, circadian rhythms (from circa diem, “about a day”) in physiology provide a means of environmental anticipation and impose oscillations in a myriad of biochemical pathways [1]. Within different organs, approximately 10%e20% of the mammalian transcriptome are under direct circadian control, signifying that these genes experience a peak in expression once every 24 h [2e4]. However, oscillations are surprisingly tissue-specific with very little overlap between organs. This indicates that a much higher percentage of genes can be expressed in a circadian manner in some part of the body. This temporal programming is concerted by intrinsic biological clocks, time-partitioning mechanisms within cells, which are present in most organisms [5]. In mammals, the circadian clock is made up of one master clock and many peripheral clocks. The master clock consists of neurons residing in the suprachiasmatic nucleus (SCN) of the brain. It is situated above the optic chiasm and receives environmental information of light and darkness via the eyes and the associated retinohypothalamic tract [6].