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Advances in human genomics, when validated functionally, can lead to new insights into how the immune system works. Notably, previously unknown mechanisms revealed by genomics can lead to the development of precision medicine unanticipated on the basis of phenotype alone.
Truncated reverse transcription of HIV RNA produces a single-stranded DNA intermediate with a unique Y-DNA stem-loop structure flanked by unpaired guanines. Schlee and colleagues show this Y-DNA activates cGAS to elicit the production of type I interferon.
Treatment with ionizing radiation can lead to the accumulation of tumor-infiltrating Treg cells. Merad and colleagues show that Langherans cells resist ionizing radiation via expression of p21 and potentiate the generation and accumulation of Treg cells.
The role of the stress-induced transcription factor ATF7 in immunity is largely unknown. Ishii and colleagues show that ATF7 represses select innate immunity–related genes, but activity is downregulated during the induction of macrophage memory.
T cells are normally dependent on TCR stimulation to be activated. Guo and colleagues now show that memory type 2 helper T cells can respond to interleukin 33 elicited by helminth infection in an TCR-independent way to induce eosinophilic inflammation.
The molecular mechanisms that lead to TH9 differentiation remain unclear. Chen and colleagues show that TGF-β- and IL-4-induced downregulation of the transcriptional repressor Id3 is required for TH9 differentiation.
V(D)J recombination is developmentally regulated and occurs at restricted sites within the genome. Clark and colleagues show that the histone reader BRWD1 is required for precise positioning of nucleosomes and targeting of RAG recombinase proteins within the Igk locus.
In the thymus, low-affinity T cell antigen receptor (TCR) engagement facilitates positive selection of the T cell repertoire. Takahama and colleagues now show TCR responsiveness of mature CD8+ T cells is fine-tuned by their affinity for positively selecting peptides in the thymus.
Paneth cell dysfunction has been linked to Crohn's disease. Nod2 and LRRK2, two genetic susceptibility factors for this disease, are now shown to have a role in regulating the sorting of lysozyme in Paneth cells and its secretion into the crypt space and, ultimately, in maintenance of the intestinal barrier.
Follicular helper T cells (TFH cells) differentiate from naive T cells, but the picture of this differentiation process remains incomplete. Two studies now identify the related transcriptional regulators TCF-1 and LEF-1 as important early participants in this process.
A previously unknown function for TH17 cell–derived IL-26 as a direct antimicrobial agent and activator of DNA-sensing innate immunity is now reported.
Intrathymic expression of self antigens is key for central tolerance. RNA-sequencing analysis of tissue-restricted antigens in individual medullary thymic epithelial cells reveals co-ordination in the gene-expression patterns that ensures effective self-representation for the production of self-tolerant T cells.