Friday, May 9, 2025
5/9/2025
Regulation of NK cell antiviral responses through alternative splicing - Project Summary/Abstract Natural killer (NK) cells have been shown to play a significant role in regulating viral infections as well as in eliminating cancerous cells. Traditionally, NK cells are classified as members of the innate immune system because of their ability to respond rapidly and non-specifically to infected or abnormal cells. Interestingly, burgeoning evidence suggests NK cells may also possess peptide-specific memory responses (previously only attributable to adaptive immunity), especially in the context of several viral infections including HIV/SIV and CMV. How NK cells can form these adaptive responses is the subject of an emerging area in immunology research, which also includes studying trained immunity of traditionally innate effectors like NK cells. Whether adaptive NK cell responses are the result of epigenetic modifications as observed in trained immunity, or the product of pre- formed polymorphic receptors like KIRs or members of the NKG2 family which interact with MHC molecules, or yet to be discovered receptors is to be determined. Here, we propose that investigating the NK cell transcriptome can provide insights into how infection or disease states can modulate NK cell function particularly by assessing how changes in alternative gene splicing following infection result in NK cell dysfunction or the formation of adaptive NK cell responses. Alternative splicing is a mechanism utilized by cells in order to produce multiple gene products from an individual gene, by splicing exons together in various combinations, sometimes leading to gene products with very different functions. Regulation of gene splicing is complicated, but it has been shown that environmental changes as are seen during viral infection or disease can gene splicing patterns. Using preliminary data from sorted NK cells in an acute SIV-infection cohort we have already identified several candidate alternatively spliced genes that exhibit differential isoform expression following SIV infection. Of particular interest are members of the bHLH transcription factor (TF) family due to their association with the formation of memory responses and NK cell development. Further, in a proof-of-concept study we have shown that NKp30 isoform expression is altered following ex vivo stimulation or even following vaccination in rhesus macaque and in human NK cell samples. Here, I propose to identify novel gene candidates and assess the roles of the bHLH TF splice variants and other candidate genes in rhesus macaque and human NK cells. Through this work I aim to determine whether specific gene isoform expression impacts normal NK cell functions or the formation of adaptive NK cell responses in vivo in rhesus macaques during acute and chronic SIV infection. The approaches outlined in this proposal will allow me to combine my postdoctoral training in NK cell biology with my predoctoral training assessing the role of alternative splicing in vivo in order to determine the roles that several gene candidates have on normal or adaptive NK cell responses during retroviral infection. Our ultimate goal is to identify and target specific isoforms to manipulate NK cell function in vivo for the purposes of improving current vaccine responses or eliciting targeted NK cell-specific therapies for HIV.
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