Wednesday, January 29, 2020

Natural Killers Responsive Through Transposable Elements

Mechanisms of immunity are generally referred through MHC, HLA, antigens and other molecules that describe the presentation and interaction of cell surface receptors with cells of the adaptive immune system. Innate immune interactions occur through inhibitory and activating receptors including on Natural Killer (NK) Cells, but rarely does research elucidate the genomic activity of the target cell and its relationship to upstream activities on the cell surface. 

Transposable Elements (TE's) are DNA sections of a gene that can change their location by insertion. They were a focus of our early work that included the study of repeats in intron's (regulatory sections of genes) and their potential relationship to protein expression. Interestingly the most recurrent TE's are among the youngest in the genomic evolutionary chain and are predominantly expressed from intergenic loci associated with antiviral or DNA damage responses. In Drosophila melanogaster, the genomic regions surrounding 84 TE's located near genes involved in stress response, behavior and development indicated an adaptive effect. Recently it has become more widely accepted that TE expression in tumors is associated with immune infiltration and increased antigenicity.

In plant immunity a TE has been domesticated for service through histone marks and generation of alternative mRNA isoforms that were both directly linked to response to a particular pathogen. In vivo, an intron1 site co-opted the TE-associated histone mark to facilitate epigenetic control of pre-mRNA processing, which established a unique mechanism for regulation of immune gene expression in plants. Although in vivo proof in animal or human cells is more complex to obtain, increasing amounts of research has been directed to determine whether TE's are a widely deployed, histone associated, epigenetic mechanism for gene expression.

p53 transcription sites evolved through epigenetic methylation, deamination and histone regulation that constituted a universal mechanism found to generate various transcription-factor binding sites in short TE's or Alu repeats. A study into the evolution of immune antigen receptor's (AgR's) originally proposed their origin from NK-like receptors that recognized MHC-like molecules. The team went on to provide evidence of such. They found that all AgR rearrangements are likely derived from the huMHCpara-19 precursor by invasion of a TE on the RAG gene that was split, by double-stranded DNA breaks (DSB) at variable (V), diversity (D), and joining (J) segments that could also be recombined. In mature NK cells recombination of the V and J element does not frequently occur, but in immature NK precursor populations RAG altered heterogeneity, cytotoxic capacity, cellular fitness and differentiation.

To persist RAG DSBs must escape efficient repair, avoid the activation of p53 cell death pathways, dissociate from their post-cleavage complex, associate with other DSBs to which they will ultimately join and successfully navigate end joining pathways. In lymphocyte precursors of scid's patients (severe combined immunodeficiency) RAG V J recombination activates a p53-dependent DNA damage checkpoint.

Mutant NK cells lacking RAG activity or Wild Type NK cells lacking a history of RAG expression are more terminally differentiated and highly cytolytic, but characterized by greater apoptosis following DNA damage. In contrast, WT NK cells with a history of RAG expression are less terminally differentiated and cytotoxic but can generate long-life memory cells following antigen-specific proliferation, characterized by increased survival and ability to repair DSBs. Therefore, an unexpected functional RAG dichotomy exists between NK cell populations to effectively combat pathogens.

Natural killer cells do not rearrange DNA to generate antigen receptors and are thus innate immune cells. However NK cells do have reciprocal relationship with cells of the adaptive immune system. The integrated dynamics of TE's in RAG DSB's and p53 binding sites implicate innate and adaptive immunity mediated through diverse NK cell population, education and antigen production possibly dating back to MHC evolution and reproductive allorecognition in which p53 plays a central role.

189 gastrointestinal cancer patients across three cancer types: 95 stomach, colorectal esophageal were examined for any aberration in DNA repair pathways that could be associated with L1 retro-transposition. Out of 15 DNA repair pathways, only the TP53 repair pathway showed a significant association. L1 retro-transposition is inversely correlated with expression of immunologic response genes. Frequent TP53 mutations in tumors with a higher load of L1 insertions suggest the critical role of TP53 in restricting retrotransposons as a guardian of L1 expression and cancer immunity.

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