Immune responses to endogenous retroelements: taking the bad with the good

Key Points Vertebrate genomes host a vast number of endogenous retroelements that exhibit distinct genomic structure, open reading frame integrity and replication autonomy or capability. Certain endogenous retroelement features have been retained to serve important immunological and non-immunological functions in the host. However, retention of 'viral' characteristics renders endogenous retroelements immunogenic. Despite targeted epigenetic silencing, many endogenous retroelements are still transcribed in adult cells and tissues. Such expression is strongly modulated in immune cells, particularly by immune stimuli. Endogenous retroelement-derived nucleic acids activate innate immune pathways, which contributes to pathologies such as systemic lupus erythematosus and Aicardi–Goutières syndrome. It also enhances responses to poorly immunogenic antigens, such as T cell-independent type 2 antigens or tumours. T cell and B cell responses to endogenous retroelement proteins are frequently detected. These adaptive responses contribute to the development of autoimmunity, but they can also lead to the targeting of abnormal cells, such as tumour cells, for destruction. Induction of endogenous retroelements by commensal colonization, pathogenic infection or cellular transformation may have evolved as an intrinsic warning system. Such beneficial contributions of immune reactivity to endogenous retroelements balance their pathogenic potential. A substantial proportion of our genome is composed of endogenous retroelements of viral origin. Such elements can retain viral characteristics and drive activation of the immune system; this can contribute to both undesirable outcomes, such as autoimmune disease, as well as beneficial responses, such as increased immune reactivity to tumours. In this Review, the authors describe the pros and the cons of these 'enemies within'. The ultimate form of parasitism and evasion of host immunity is for the parasite genome to enter the germ line of the host species. Retroviruses have invaded the host germ line on the grandest scale, and this is evident in the extraordinary abundance of endogenous retroelements in the genome of all vertebrate species that have been studied. Many of these endogenous retroelements have retained viral characteristics; some also the capacity to replicate and, consequently, the potential to trigger host innate and adaptive immune responses. However, although retroelements are mainly recognized for their pathogeni