Biology subjects

Garner, L. C.

Publications and source records attributed to Garner, L. C..

6 recordsLinked to original sources

bioRxiv2026

CXCR3 on transferred T cells enables vaccine-boosted adoptive T-cell therapy in solid tumors

Adoptive T-cell therapy (ACT) has demonstrated marked clinical benefit in hematological malignancies but has limited efficacy against solid tumors. Cancer vaccines can improve ACT, but the mechanisms underlying this combination are poorly understood. Here, we combined ACT with chimpanzee adenovirus ChAdOx1 (ChAd) and modified vaccinia Ankara (MVA) encoding tumor antigens. Whereas PD1 blockade failed to improve ACT, the combination with ChAd/MVA vaccination drove durable regression of established tumors, correlating with expansion of tumor-reactive T cells in lymphoid organs and increased tumor infiltration by T cells. Mechanistically, ChAd priming induced CXCR3 ligands (CXCL10 and CXCL9) in the vaccine-draining lymph node, thereby recruiting transferred T cells to this node independently of cognate antigen. CXCR3 expression on the transferred T cells, but not on host cells, was required for the anti-tumor effect of the combination therapy and favored T-cell accumulation in the vaccine-draining lymph node and the tumor. These findings identify CXCR3 on the transferred T cells as a determinant of ACT plus vaccination synergy and provide a rationale for combining viral-vector vaccines with TCR-T therapies, and for selecting or engineering T cells to retain CXCR3 expression.

immunology↗

bioRxiv2025

Single-cell profiling of blood and cerebrospinal fluid in tuberculous meningitis

Tuberculous meningitis (TBM) is the most severe form of tuberculosis, with a fatality rate of 20-50% in treated individuals. Although corticosteroid therapy can increase survival in HIV-negative people with TBM, better antimicrobial and host-directed therapies are required to improve outcome. There is, therefore, a need to better understand local immunopathologic pathways. Despite its power in identifying disease-specific cellular profiles, single-cell RNA-sequencing (scRNA-seq) has been underutilized in cerebral samples in brain infection. We employed scRNA-seq to analyze fresh pretreatment cerebrospinal fluid (CSF) from four TBM patients, along with paired peripheral blood mononuclear cells (PBMCs). While 29 cell subtypes were present in both tissues, their relative abundance varied significantly. In particular, CSF was enriched with highly inflammatory microglia-like macrophages, GZMK-expressing CD8+ T cells, and CD56bright NK cells. The latter two subsets exhibited features associated with dysfunctional cytotoxicity. Across multiple cell types, inflammatory signaling pathways were increased and oxidative phosphorylation was decreased in CSF compared to PBMCs. This study highlights the value of scRNA-seq for exploring CSF immunopathogenesis in TBM patients and offers a resource for future studies investigating the pathophysiology of TBM and other brain infections, including potentially targetable cell populations linked with immune-mediated pathology.

immunology↗

bioRxiv2024

Early NK-cell and T-cell dysfunction marks progression to severe dengue in patients with obesity and healthy weight

Dengue is a mosquito-borne virus infection affecting half of the worlds population for which therapies are lacking. The role of T and NK-cells in protection/immunopathogenesis remains unclear for dengue. We performed a longitudinal phenotypic, functional and transcriptional analyses of T and NK-cells in 124 dengue patients using flow cytometry and single-cell RNA-sequencing. We show that T/NK-cell signatures early in infection discriminate patients who will progress to severe dengue (SD) from those who do not. In patients with overweight/obesity these signatures are exacerbated compared to healthy weight patients, supporting their increased susceptibility to SD. In SD, CD4+/CD8+ T-cells and NK-cells display increased co-inhibitory receptor expression and decreased cytotoxic capacity compared to non-SD. Furthermore, type-I Interferon signalling is downregulated in SD, suggesting defective virus-sensing mechanisms may underlie NK/T-cell dysfunction. We propose that dysfunctional "professional killer" T/NK-cells underpin dengue pathogenesis. Our findings pave the way for the evaluation of immunomodulatory therapies for dengue.

immunology↗

bioRxiv2022

A conserved population of MHC II-restricted, innate-like, commensal-reactive T cells in the gut of humans and mice

Interactions with commensal microbes shape host immunity on multiple levels and are recognized to play a pivotal role in human health and disease. In this study, we show that MHC-II restricted, commensal-reactive T cells in the colon of both humans and mice acquire transcriptional and functional characteristics typically associated with innate-like T cells, including the expression of the key transcription factor PLZF and the ability to respond to cytokines including IL-12, IL-18 and IL-23 in a TCR-independent manner. These MHC-II restricted, innate-like, commensal-reactive T cells (TMIC) are endowed with a polyfunctional effector potential spanning classic Th1- and Th17-cytokines, cytotoxic molecules as well as regulators of epithelial homeostasis and represent an abundant and conserved cell population in the human and murine colon. T cells with the TMIC phenotype were increased in ulcerative colitis patients and their presence aggravated pathology in DSS-treated mice, pointing towards a pathogenic role in colitis. Our findings add TMIC cells to the expanding spectrum of innate-like immune cells positioned at the frontline of intestinal immune surveillance, capable of acting as sentinels of microbes and the local cytokine milieu.

immunology↗

bioRxiv2022

Human MAIT cells show clonal diversity but transcriptional and functional homogeneity

Mucosal-associated invariant T (MAIT) cells are considered to have limited clonal diversity. In contrast, recent studies suggest the presence of functionally distinct subsets. We investigated this model through single-cell analysis of the MAIT cell TCR repertoire and transcriptional profile in human blood and liver. Further, we developed functional RNA-sequencing (fRNA-seq), an approach to integrate cellular function and TCR clonotype at a single-cell level following differential stimulation. MAIT cells showed surprising clonal diversity, with TCR repertoires shared across tissues but unique to individuals. Functional diversity within resting MAIT cells was low and largely related to tissue site. MAIT cells displayed distinct transcriptional responses to in vitro TCR and cytokine stimulation, with cells positioned along gradients of activation. Clonal origin influenced both resting and activated transcriptional profiles. Overall, MAIT cells exhibit diverse donor-specific TCR repertoires which, along with tissue and activation context, influence their phenotype and function.

immunology↗

bioRxiv2019

Human intestinal tissue-resident memory CD8+ T cells comprise transcriptionally and functionally distinct subsets

Tissue-resident memory T (TRM) cells provide key adaptive immune responses in infection, cancer, and autoimmunity. However transcriptional heterogeneity of human intestinal TRM cells remains undefined, and definitive markers of CD103-TRM cells are lacking. Here, we investigated transcriptional and functional heterogeneity of human TRM cells through the study of donor-derived intestinal TRM cells from intestinal transplant recipients. Single-cell transcriptional profiling identified four conventional TRM populations, with two distinct transcriptional states of CD8+ TRM cells, delineated by ITGAE and ITGB2 expression. We defined a transcriptional signature discriminating the two CD8+ populations, including differential expression of key residency-associated genes and cytotoxic molecules. Flow cytometry of recipient-derived cells infiltrating the graft and intestinal lymphocytes from healthy gut confirmed the two CD8+ TRM phenotypes, with {beta}2-integrin acting as a CD103-CD8+ TRM marker. CD103+ CD8+ TRM cells produced IL-2, and demonstrated greater polyfunctional cytokine production, while {beta}2-integrin+ CD69+ CD103-TRM cells had higher granzyme expression. Phenotypic and functional analysis of intestinal CD4+ T cells identified many parallels, including a distinct {beta}2-integrin+ population. Together, these results describe the transcriptional, phenotypic, and functional heterogeneity of human intestinal TRM cells, and suggest a role for {beta}2-integrin in TRM development. SummaryHeterogeneity within human tissue-resident memory T (TRM) cells is poorly understood. We show that transcriptionally, phenotypically, and functionally distinct CD4+ and CD8+ TRM subsets exist in the human intestine, and that {beta}2-integrin expression identifies a distinct population of CD8+ TRM cells.

immunology↗