Biology subjects

Asiimwe, R.

Publications and source records attributed to Asiimwe, R..

4 recordsLinked to original sources

bioRxiv2025

A developmental program of early residency promotes the differentiation of divergent uterine NK cell subsets in humans

Human uterine natural killer cells (uNKs) are a tissue-resident, innate lymphocyte population that have critical roles in supporting pregnancy health. uNKs derive from circulatory cells in the peripheral blood which immigrate into the endometrium and become resident as they reconstitute the uterine lining after menses. How tissue-resident uterine NK cells arise from blood-based precursor cells is unknown. Here, we identify early tissue immigrants, developmental intermediates, and mature effector states in human endometrium. We also uncover a transcriptional program of TGF-{beta} responsive genes that is upregulated in recent tissue immigrants prior to expression of effector molecules. Differences in TGF-{beta} responsiveness of uNK precursors promote differential expression of divergent effector uNK subsets, resulting in either repression or preservation of cytotoxic effector potential. Collectively, these data suggest a molecular mechanism of tissue-resident uNK maturation that links tissue residency with the acquisition of divergent effector functions in human endometrium.

immunology↗

bioRxiv2024

Inhibition of NFAT promotes loss of tissue resident uterine natural killer cells and attendant pregnancy complications in humans

Uterine natural killer cells (uNKs) are a tissue resident lymphocyte population that are critical for pregnancy success. Although mouse models have demonstrated that NK deficiency results in abnormal placentation and poor pregnancy outcomes, the generalizability of this knowledge to humans remains unclear. Here we identify uterus transplant (UTx) recipients as a human population with reduced uNK cells and altered pregnancy phenotypes. We show that the NK reduction in UTx correlates with impaired transcriptional programming of NK tissue residency arising from the inhibition of NFAT-mediated signaling. Our observations suggest that NFAT-dependent genes modulate multiple molecular tissue residency programs in uNKs. These include early residency programs involving AP-1-family transcription factors and TGF-{beta}-mediated upregulation of surface integrins. Collectively, our data identify a previously undescribed role for NFAT in uterine NK tissue residency and provide novel mechanistic insights into the biologic basis of pregnancy complications due to alteration of tissue resident NK subsets in humans. One Sentence SummaryRole of NFAT in uterine NK cell tissue residency

immunology↗

bioRxiv2024

Sequential Transcriptional Programs of Tissue Residency Drive Human Uterine NK Cell Development

Uterine natural killer cells are critical for pregnancy success, but the origin and development of these cells in humans remain unclear. Here we use various single cell approaches to identify the transcriptional programs governing uterine NK cell development in humans. These analyses suggest a developmental continuum which begins with seeding of the endometrium with blood immature CD56bright precursors, evolves through CD56bright endometrial founder NK cells, and ends with tissue resident decidual NK cells during pregnancy which possess non-cytotoxic functions. Our work identifies a role for sequential programs of tissue residency in the differentiation of these cells, as differentiating endometrial tissue resident NK (trNK) cells acquire early and late transcriptional programs of residency which coincide with acquisition of unique non-cytotoxic effector programs. Notably, we identified early residency programs in human endometrial trNKs by expression of NR4A2, AP-1 transcription factors, and other immediate early response genes that were shared with CD8 tissue resident memory T cells in mice, suggesting conservation of transcriptional programs of early tissue residency programs across species and cell types. Late residency programs were guided by TGF{beta}, which promoted expression of various integrins and trNK subset diversification within the non-pregnant endometrium. Altogether, these data identify the molecular foundations for endometrial trNK heterogeneity and suggest that the uterine NK diversity observed during pregnancy is established before embryo implantation and intimately tied to residency programming.

immunology↗

bioRxiv2024

STAR+WASP reduces reference bias in the allele-specific mapping of RNA-seq reads

SummaryAllele-specific expression (ASE) is an important genetic phenomenon that impacts an individuals phenotype and is relevant in various biological and medical contexts. Next-generation RNA sequencing technologies provide an unprecedented opportunity to measure ASE genome-wide across all heterozygous alleles expressed in a given sample. One of the major obstacles to the accurate calculation of ASE from RNA-seq data is the reference mapping bias, i.e., the preferential misalignment of the reads to the reference allele. Here, we present STAR+WASP, our reimplementation of WASP, a highly accurate algorithm for reducing the reference bias (Van De Geijn et al. 2015). We show that STAR+WASP is an order of magnitude faster than WASP while significantly reducing reference bias and providing ASE estimations similar to the original WASP algorithm. Availability and ImplementationSTAR+WASP is implemented within STAR as an integrated C++ module. STAR+WASP is open-source software, freely accessible at: http://code.google.com/p/rna-star/. Contactdobin@cshl.edu Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗