Biology subjects

Cook, M. C.

Publications and source records attributed to Cook, M. C..

4 recordsLinked to original sources

bioRxiv2026

In vivo screening reveals new regulators of Natural Killer cell development and functional response to acute cytomegalovirus infection

Natural killer (NK) cells are critical innate immune effectors in antiviral and antitumour responses. However, the factors governing NK cell development and function remain incompletely understood. To address this, we adopted an in vivo screening approach, generating a panel of mice deficient in genes differentially expressed across NK cell maturation stages or following viral infection. We performed a combinational screen comprising baseline immunophenotyping and mouse cytomegalovirus (MCMV) challenge. We identified novel regulators of NK cell development, including transcriptional regulators and proteins with putative trafficking functions. MCMV challenge studies additionally identified proteins that impacted antiviral immunity independently of NK cell phenotypes, including a novel regulator of NK cell degranulation, Synaptotagmin-like protein 3. Identified genes exhibited reduced tolerance to loss-of-function in large scale human sequencing studies and evidence for reduced NK cell numbers in a cohort of immunodeficiency patients. Together, these findings provide a resource of NK-expressed genes important for NK cell maturation and function, with relevance to human health. SummaryPring et al. conduct an in vivo screen in mice identifying novel regulators of natural killer (NK) cell development and/or antiviral functionality. Large-scale human sequencing and human immunodeficiency patients revealed evidence for the relevance of identified genes in human health.

immunology↗

bioRxiv2023

Rare SH2B3 coding variants identified in lupus patients impair B cell tolerance and predispose to autoimmunity

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease, with a clear genetic component. While most SLE patients carry rare gene variants in lupus risk genes, little is known about their contribution to disease pathogenesis. Amongst them, SH2B3 - a negative regulator of cytokine and growth factor receptor signaling - harbors rare coding variants in over 5% of SLE patients. Here we show that unlike the variant found exclusively in healthy controls, most SH2B3 rare variants found in lupus patients are predominantly hypomorphic alleles. Generation of two mouse lines carrying variants orthologous to those found in patients revealed SH2B3 is important to limit the numbers of immature and transitional B cells. Furthermore, hypomorphic SH2B3 was shown to impair negative selection of immature/transitional self-reactive B cells and accelerate autoimmunity in sensitized mice, at least in part due to increased IL-4R signaling and BAFF-R expression. This work identifies a previously unappreciated role for SH2B3 in human B cell tolerance and lupus risk. SummaryZhang et al. reveal a role for hypomorphic SH2B3 in lupus risk. The study shows rare and damaging variants identified in lupus patients enable breach of B cell immune tolerance checkpoints and suggests involvement for dysregulated IL-4R signaling and BAFF-R expression.

immunology↗

bioRxiv2022

ZEB2 regulates the development of CD11c+ atypical B cells

CD11c+ atypical B cells (ABC) are an alternative memory B cell lineage identified both in normal immune responses as well as pathogenic responses in autoimmunity. While it is clear that ABCs have a distinct transcriptional program, the factors that direct this program have not been identified. Here, we generated a human tonsil single-cell RNA-seq dataset and identified candidate transcription factors associated with the ABC population. We selected 8 of these transcription factors for further analysis based on their conserved expression in mouse ABC bulk RNA-seq datasets. Using an optimized CRSPR-Cas9 knockdown method we found that only zinc finger E-box binding homeobox 2 (Zeb2) knock-out impaired ABC formation. To assess the role of Zeb2 in ABC formation in vivo we used Zeb2fl/fl mice crossed to a CD23Cre line. Germinal center and plasma cell responses in these mice after Plasmodium sporozoite immunization were largely unaltered but we observed a specific defect in ABC formation. We further determined that ZEB2 haploinsufficient Mowat Wilson syndrome patients also have decreased circulating ABCs in the blood, supporting a role for this transcription factor in humans as well as mice. In sum, we identified Zeb2 as a key TF governing the formation of ABCs.

immunology↗

bioRxiv2017

Cleaning clinical genomic data: Simple identification and removal of recurrently miscalled variants in single genomes

Identification of sequence variation from short-read sequence data is subject to common-yet-intermittent miscalling that occurs in a sequence intrinsic manner. We identify that recurrent false positive single nucleotide variants are strongly present in databases of human sequence variation and demonstrate how each individual sample generates a unique set of recurrent false positive variants. These recurrent miscalls result from known difficulties aligning short-read sequence data between redundant genomic regions. We could replicate, catalogue and remove three quarters of these recurrent miscalls for any given exome with as little as ten rounds of read resampling, realignment and recalling. The removal of such misleading variants reduces the search space for identification of disease causing variants.\n\nList of Abbreviations

genomics↗