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Multimodal single-cell analysis of cutaneous T cell lymphoma reveals distinct sub-clonal tissue-dependent signatures

Herrera, Alberto; Cheng, Anthony; Mimitou, Eleni P; Seffens, Angelina; George, Dean David; Bar-Natan, Michal; Heguy, Adriana; Ruggles, Kelly V; Scher, Jose U; Hymes, Kenneth; Latkowski, Jo-Ann; Odum, Niels; Kadin, Marshall E; Ouyang, Zhengqing; Geskin, Larissa; Smibert, Peter; Buus, Terkild B; Koralov, Sergei
Cutaneous T cell lymphoma (CTCL) is a heterogeneous group of mature T cell neoplasms characterized by the accumulation of clonal malignant CD4+ T cells in the skin. The most common variant of CTCL, Mycosis Fungoides, is confined to the skin in early stages but can be accompanied by extracutaneous dissemination of malignant T cells to the blood and lymph nodes in advanced stages of disease. Sézary Syndrome, a leukemic form of disease is characterized by significant blood involvement. Little is known about the transcriptional and genomic relationship between skin and blood residing malignant T cells in CTCL. To identify and interrogate malignant clones in matched skin and blood from leukemic MF and SS patients, we combine T cell receptor clonotyping, with quantification of gene expression and cell surface markers at the single cell level. Our data reveals clonal evolution at a transcriptional and genetic level within the malignant populations of individual patients. We highlight highly consistent transcriptional signatures delineating skin-derived and blood-derived malignant T cells. Analysis of these two populations suggests that environmental cues, along with genetic aberrations, contribute to transcriptional profiles of malignant T cells. Our findings indicate that the skin microenvironment in CTCL promotes a transcriptional response supporting rapid malignant expansion, as opposed to the quiescent state observed in the blood, potentially influencing efficacy of therapies. These results provide insight into tissue-specific characteristics of cancerous cells and underscore the need to address the patients' individual malignant profiles at the time of therapy to eliminate all sub-clones.
PMID: 34232982
ISSN: 1528-0020
CID: 4932182

Multiplexed detection of proteins, transcriptomes, clonotypes and CRISPR perturbations in single cells

Mimitou, Eleni P; Cheng, Anthony; Montalbano, Antonino; Hao, Stephanie; Stoeckius, Marlon; Legut, Mateusz; Roush, Timothy; Herrera, Alberto; Papalexi, Efthymia; Ouyang, Zhengqing; Satija, Rahul; Sanjana, Neville E; Koralov, Sergei B; Smibert, Peter
Multimodal single-cell assays provide high-resolution snapshots of complex cell populations, but are mostly limited to transcriptome plus an additional modality. Here, we describe expanded CRISPR-compatible cellular indexing of transcriptomes and epitopes by sequencing (ECCITE-seq) for the high-throughput characterization of at least five modalities of information from each single cell. We demonstrate application of ECCITE-seq to multimodal CRISPR screens with robust direct single-guide RNA capture and to clonotype-aware multimodal phenotyping of cancer samples.
PMID: 31011186
ISSN: 1548-7105
CID: 3821452

Augmented Th17 Differentiation Leads to Cutaneous and Synovio-Entheseal Inflammation in a Novel Model of Psoriatic Arthritis

Yang, Lu; Fanok, Melania H; Mediero-Munoz, Aranzazu; Fogli, Laura K; Corciulo, Carmen; Abdollahi, Shahla; Cronstein, Bruce N; Scher, Jose U; Koralov, Sergei B
OBJECTIVE:CD4Cre mice, and investigate the role of Th17 cytokines in the disease pathogenesis. METHODS:CD4Cre mice onto an IL-22 knockout background or treating them with a neutralizing antibody against IL-17, we interrogated how these Th17 cytokines contribute to disease pathogenesis. RESULTS:CD4Cre mice, revealing a central role of Th17 cells in the regulation of OCP numbers and RANKL expression on stromal cells. CONCLUSION/CONCLUSIONS:CD4Cre mice, leading to cutaneous and synovio-entheseal inflammation, and bone pathology highly reminiscent of psoriatic arthritis. Both IL-17A and IL-22 produced by Th17 cells play critical roles in promoting the cutaneous and musculoskeletal inflammation that characterizes psoriatic arthritis..
PMCID:5984671
PMID: 29439292
ISSN: 2326-5205
CID: 2958282

miRNAs Are Essential for the Regulation of the PI3K/AKT/FOXO Pathway and Receptor Editing during B Cell Maturation

Coffre, Maryaline; Benhamou, David; Riess, David; Blumenberg, Lili; Snetkova, Valentina; Hines, Marcus J; Chakraborty, Tirtha; Bajwa, Sofia; Jensen, Kari; Chong, Mark M W; Getu, Lelise; Silverman, Gregg J; Blelloch, Robert; Littman, Dan R; Calado, Dinis; Melamed, Doron; Skok, Jane A; Rajewsky, Klaus; Koralov, Sergei B
B cell development is a tightly regulated process dependent on sequential rearrangements of immunoglobulin loci that encode the antigen receptor. To elucidate the role of microRNAs (miRNAs) in the orchestration of B cell development, we ablated all miRNAs at the earliest stage of B cell development by conditionally targeting the enzymes critical for RNAi in early B cell precursors. Absence of any one of these enzymes led to a block at the pro- to pre-B cell transition due to increased apoptosis and a failure of pre-B cells to proliferate. Expression of a Bcl2 transgene allowed for partial rescue of B cell development, however, the majority of the rescued B cells had low surface immunoglobulin expression with evidence of ongoing light chain editing. Our analysis revealed that miRNAs are critical for the regulation of the PTEN-AKT-FOXO1 pathway that in turn controls Rag expression during B cell development.
PMCID:5679080
PMID: 27880903
ISSN: 2211-1247
CID: 2314502

Targeting leukocidin-mediated immune evasion protects mice from Staphylococcus aureus bacteremia

Tam, Kayan; Lacey, Keenan A; Devlin, Joseph C; Coffre, Maryaline; Sommerfield, Alexis; Chan, Rita; O'Malley, Aidan; Koralov, Sergei B; Loke, P'ng; Torres, Victor J
Staphylococcus aureus is responsible for various diseases in humans, and recurrent infections are commonly observed. S. aureus produces an array of bicomponent pore-forming toxins that target and kill leukocytes, known collectively as the leukocidins. The contribution of these leukocidins to impair the development of anti-S. aureus adaptive immunity and facilitate reinfection is unclear. Using a murine model of recurrent bacteremia, we demonstrate that infection with a leukocidin mutant results in increased levels of anti-S. aureus antibodies compared with mice infected with the WT parental strain, indicating that leukocidins negatively impact the generation of anti-S. aureus antibodies in vivo. We hypothesized that neutralizing leukocidin-mediated immune subversion by vaccination may shift this host-pathogen interaction in favor of the host. Leukocidin-immunized mice produce potent leukocidin-neutralizing antibodies and robust Th1 and Th17 responses, which collectively protect against bloodstream infections. Altogether, these results demonstrate that blocking leukocidin-mediated immune evasion can promote host protection against S. aureus bloodstream infection.
PMID: 32602902
ISSN: 1540-9538
CID: 4504062

The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids

Cao, Wei; Kayama, Hisako; Chen, Mei Lan; Delmas, Amber; Sun, Amy; Kim, Sang Yong; Rangarajan, Erumbi S; McKevitt, Kelly; Beck, Amanda P; Jackson, Cody B; Crynen, Gogce; Oikonomopoulos, Angelos; Lacey, Precious N; Martinez, Gustavo J; Izard, Tina; Lorenz, Robin G; Rodriguez-Palacios, Alex; Cominelli, Fabio; Abreu, Maria T; Hommes, Daniel W; Koralov, Sergei B; Takeda, Kiyoshi; Sundrud, Mark S
PMID: 32187521
ISSN: 1097-4180
CID: 4352762

miR-29 Sustains B Cell Survival and Controls Terminal Differentiation via Regulation of PI3K Signaling

Hines, Marcus J; Coffre, Maryaline; Mudianto, Tenny; Panduro, Marisella; Wigton, Eric J; Tegla, Cosmin; Osorio-Vasquez, Victoria; Kageyama, Robin; Benhamou, David; Perez, Oriana; Bajwa, Sofia; McManus, Michael T; Ansel, K Mark; Melamed, Doron; Koralov, Sergei B
The phosphatidylinositol 3-kinase (PI3K) signaling cascade downstream of the B cell receptor (BCR) signalosome is essential for B cell maturation. Proper signaling strength is maintained through the PI3K negative regulator phosphatase and tensin homolog (PTEN). Although a role for microRNA (miRNA)-dependent control of the PTEN-PI3K axis has been described, the contribution of individual miRNAs to the regulation of this crucial signaling modality in mature B lymphocytes remains to be elucidated. Our analyses reveal that ablation of miR-29 specifically in B lymphocytes results in an increase in PTEN expression and dampening of the PI3K pathway in mature B cells. This dysregulation has a profound impact on the survival of B lymphocytes and results in increased class switch recombination and decreased plasma cell differentiation. Furthermore, we demonstrate that ablation of one copy of Pten is sufficient to ameliorate the phenotypes associated with miR-29 loss. Our data suggest a critical role for the miR-29-PTEN-PI3K regulatory axis in mature B lymphocytes.
PMID: 33264610
ISSN: 2211-1247
CID: 4694202

Role of dysregulated cytokine signaling and bacterial triggers in the pathogenesis of Cutaneous T Cell Lymphoma

Fanok, Melania H; Sun, Amy; Fogli, Laura K; Narendran, Vijay; Eckstein, Miriam; Kannan, Kasthuri; Dolgalev, Igor; Lazaris, Charalampos; Heguy, Adriana; Laird, Mary E; Sundrud, Mark S; Liu, Cynthia; Kutok, Jeff; Lacruz, Rodrigo S; Latkowski, Jo-Ann; Aifantis, Iannis; Odum, Niels; Hymes, Kenneth B; Goel, Swati; Koralov, Sergei B
Cutaneous T cell lymphoma is a heterogeneous group of lymphomas characterized by the accumulation of malignant T cells in the skin. The molecular and cellular etiology of this malignancy remains enigmatic and what role antigenic stimulation plays in the initiation and/or progression of the disease remains to be elucidated. Deep sequencing of the tumor genome revealed a highly heterogeneous landscape of genetic perturbations and transcriptome analysis of transformed T cells further highlighted the heterogeneity of this disease. Nonetheless, using data harvested from high-throughput transcriptional profiling allowed us to develop a reliable signature of this malignancy. Focusing on a key cytokine signaling pathway, previously implicated in CTCL pathogenesis, JAK/STAT signaling, we used conditional gene targeting to develop a fully penetrant small animal model of this disease that recapitulates many key features of mycosis fungoides, a common variant of CTCL. Using this mouse model, we demonstrate that T cell receptor engagement is critical for malignant transformation of the T lymphocytes and that progression of the disease is dependent on microbiota.
PMCID:5912980
PMID: 29128259
ISSN: 1523-1747
CID: 2785082

Role of Antigenic Stimulation in Cutaneous T-Cell Lymphomas

Gumina, Megan E; Hooper, Madeline J; Zhou, Xiaolong A; Koralov, Sergei B
Cutaneous T-cell lymphoma (CTCL) involves a clonal expansion of malignant cells accumulating in the skin, a primary barrier site. CTCL has long been hypothesized to be caused or perpetuated by chronic antigen stimulation due to unknown exposures. These antigenic triggers, defined as any element that may cause activation of malignant T cells through TCR signaling, have been hypothesized to range from chemicals to microbes. This review covers current evidence supporting chemical and microbial stimuli that may act as antigenic triggers of CTCL and summarizes novel areas of investigation, in which the potential antigenicity of the exposure is still unknown.
PMID: 38149950
ISSN: 1523-1747
CID: 5623182

mRNA COVID-19 vaccine elicits potent adaptive immune response without the acute inflammation of SARS-CoV-2 infection

Ivanova, Ellie N.; Shwetar, Jasmine; Devlin, Joseph C.; Buus, Terkild B.; Gray-Gaillard, Sophie; Koide, Akiko; Cornelius, Amber; Samanovic, Marie I.; Herrera, Alberto; Mimitou, Eleni P.; Zhang, Chenzhen; Karmacharya, Trishala; Desvignes, Ludovic; Ødum, Niels; Smibert, Peter; Ulrich, Robert J.; Mulligan, Mark J.; Koide, Shohei; Ruggles, Kelly V.; Herati, Ramin S.; Koralov, Sergei B.
SARS-CoV-2 infection and vaccination elicit potent immune responses. Our study presents a comprehensive multimodal single-cell analysis of blood from COVID-19 patients and healthy volunteers receiving the SARS-CoV-2 vaccine and booster. We profiled immune responses via transcriptional analysis and lymphocyte repertoire reconstruction. COVID-19 patients displayed an enhanced interferon signature and cytotoxic gene upregulation, absent in vaccine recipients. B and T cell repertoire analysis revealed clonal expansion among effector cells in COVID-19 patients and memory cells in vaccine recipients. Furthermore, while clonal αβ T cell responses were observed in both COVID-19 patients and vaccine recipients, expansion of clonal γδ T cells was found only in infected individuals. Our dataset enables side-by-side comparison of immune responses to infection versus vaccination, including clonal B and T cell responses. Our comparative analysis shows that vaccination induces a robust, durable clonal B and T cell responses, without the severe inflammation associated with infection.
SCOPUS:85179086246
ISSN: 2589-0042
CID: 5620862