Expression of Human Endogenous Retroviruses in the Human Thymus Along T Cell Development

Abstract

Human Endogenous Retroviruses (HERVs) constitute up to 8% of the human genome and have been emerging as important modulators of the immune system, being associated with cancer, autoimmunity and infectious diseases. Here, we investigated the expression of three HERV families in the human thymus. HERV-K, -W, and -R envelope (env) and HERV-K gag transcriptional levels were quantified in the main thymocyte subsets, thymic epithelial cells (TECs), B cells and myeloid populations, and Env protein expression was studied in thymic tissue. We found that HERV mRNA decreased with T cell development, which was in agreement with the identification of HERV-K Env protein in CD3 negative cortical cells. These results suggest a distinct regulation of HERV expression along T cell development, prompting us to evaluate the interplay with host restriction factors and potential underlying pathways. The transcriptional levels of some HERVs were found to positively correlate with the expression of the host restriction factors APOBEC3G and SLFN11, and, conversely, a negative correlation was found with SAMHD1. Moreover, IFN-α and IFN-γ induced the upregulation of HERV-K env and gag in purified CD4 single-positive thymocytes. Additionally, we found high levels of HERV mRNAs in TECs. Overall, our data support a tight regulation of HERV expression during human T cell development, with possible implications for the process of T cell selection.

Thymus antibody-secreting cells possess an interferon gene signature and are preferentially expanded in young female mice

“…In considering how the THY environment may shape resident ASC function, an open question is the potential source of IFN-inducing pathogen associated molecular patterns as well as the cellular sources of IFN in the THY. Endogenous retroviruses (ERVs) can be found in both the human 96 and mouse 71 THY and intact TLR signaling, in particularly TLR7, is critical in preventing reactivation of these ERVs. 71 As TLR7 signaling is a potent inducer of Type I IFN, this regulatory loop would explain the constitutive IFN-α expression in the human THY.…”

Elimination of virus-like particles reduces protein aggregation and extends replicative lifespan in Saccharomyces cerevisiae

“…It has been estimated that human endogenous retroviruses make up 4 to 8% of the human genome ( 71 ). They have also been shown to be expressed in several cell lineages, including stem cells ( 72 ). It is therefore possible that expression of these endogenous retroviruses could have similar detrimental effects on human cells, especially during aging.…”

Thymus antibody-secreting cells: once forgotten but not lost

“…As thymocyte apoptosis regulates the production of regulatory T cells ( 97 ), it is plausible that ssRNA is released to the extracellular environment during this process. In addition, reactivation of endogenous retroviruses within the THY could also provide the requisite TLR ligands ( 98 , 99 ). Subsequently, the IFN responsive phenotype can be maintained by extrinsically derived IFNs (e.g., pDCs) ( Figure 2C ) or alternatively, by IFNs intrinsically produced by TLR7 stimulated THY B cells and ASCs ( Figure 2D ).…”