Biology subjects

Musial, S. C.

Publications and source records attributed to Musial, S. C..

6 recordsLinked to original sources

bioRxiv2026

Common viral infections seed regionally distinct resident memory T cells in the human CNS

T cells persist in the central nervous system (CNS) and can drive both protection and neurological disease. How these cells are organized in humans and what they recognize is largely unknown. Here, we profiled CD8 T cells across anatomically distinct CNS regions, obtained through on-site autopsies and temporal lobe resection surgeries, using single-cell RNA sequencing, paired T cell receptor sequencing, and DNA-barcoded tetramers. Resident memory T cells (TRM) specific for Epstein-Barr virus, cytomegalovirus, influenza A, and SARS-CoV-2 were identified across CNS compartments. Anatomical location was the strongest correlate of TRM cell state, with leptomeningeal cells adopting a cytokine-poised TRM program, whereas brain TRM cells were transcriptionally restrained. Cells of the same clonotype spanned tissues yet adopted local transcriptional states. Viral specificity added another layer of TRM heterogeneity with GZMK/GZMA-expressing EBV-specific populations and interferon-stimulated gene signatures in SARS-CoV-2 and Influenza A-specific cells. The human CNS thus harbors regionally distinct CD8+ TRM shaped by common viral exposures.

immunology↗

bioRxiv2026

Circulating and brain-resident memory CD8+ T cells seed distinct bystander TRM-like populations in glioblastoma

Across cancers, tumor-infiltrating CD8+ T cells expressing the tissue-resident memory T cell (TRM) markers CD69 and CD103 are strongly associated with favorable clinical outcomes. However, a substantial fraction of these cells in human tumors are not tumor-specific, but instead recognize unrelated viral antigens. These virus-specific bystander TRM-like cells are prevalent in tumors and retain functional potential, raising interest in strategies that leverage pre-existing antiviral immunity for cancer immunotherapy. Yet their origins and differentiation states remain poorly defined, limiting both the interpretation of residency-based tumor-infiltrating lymphocyte (TIL) phenotyping and efforts to rationally harness these TRM-like cells. Here, using mouse models of GBM and melanoma, we demonstrate that resting circulating memory T cells trafficked into tumors via GPCR-dependent signaling and rapidly adopted a tissue-resident phenotype, independent of cognate antigen. Strikingly, in GBM, but not melanoma, pre-existing brain TRM contributed substantially to the bystander TIL compartment and were the dominant source of CD69+/CD103+ bystander T cells, revealing a tumor- and tissue-specific origin for this subset. These findings were further supported by transcriptional analysis of T cell receptor clones present in both paired patient GBM tumor and peritumoral brain, which identified shared features with TRM-derived TILs in mouse GBM. Overall, this work provides new insight into tumor immunosurveillance, inform the interpretation of CD69+/CD103- and CD103+ TIL populations, and lay a foundation for immunotherapeutic strategies aimed at harnessing circulating and pre-existing virus-specific TRM populations in tumors.

immunology↗

bioRxiv2024

Alarm functions of PD-1+ brain resident memory T cells

Resident memory T cells (TRM) have been described in barrier tissues as having a sensing and alarm function where, upon sensing cognate antigen, they alarm the surrounding tissue and orchestrate local recruitment and activation of immune cells. In the immunologically unique and tightly restricted CNS, it remains unclear if and how brain TRM, which express the inhibitory receptor PD-1, alarm the surrounding tissue during antigen re-encounter. Here, we reveal that TRM are sufficient to drive the rapid remodeling of the brain immune landscape through activation of microglia, DCs, NK cells, and B cells, expansion of Tregs, and recruitment of macrophages and monocytic dendritic cells. Moreover, we report that while PD-1 restrains granzyme B expression by reactivated brain TRM, it has no effect on cytotoxicity or downstream alarm responses. We conclude that TRM are sufficient to trigger rapid immune activation and recruitment in the CNS and may have an unappreciated role in driving neuroinflammation.

immunology↗

bioRxiv2024

CD39 is expressed on functional effector and tissue resident memory CD8+ T cells

The ecto-ATPase CD39 is expressed on exhausted CD8+ T cells in chronic viral infection and has been proposed as a marker of tumor-specific CD8+ T cells in cancer, but the role of CD39 in an effector and memory T cell response has not been clearly defined. We report that CD39 is expressed on antigen-specific CD8+ short-lived effector cells (SLECs), while its co-ecto-enzyme, CD73, is found on memory precursor effector cells (MPEC) in vivo. Inhibition of CD39 enzymatic activity during in vitro T cell priming enhances MPEC differentiation in vivo after transfer and infection. The enriched MPEC phenotype is associated with enhanced tissue resident memory (TRM) establishment in the brain and salivary gland following an acute intranasal viral infection, suggesting that CD39 ATPase activity plays a role in memory CD8+ T cell differentiation. We also show that CD39 is expressed on human and murine TRM across several non-lymphoid tissues and melanoma, while CD73 is expressed on both circulating and resident memory subsets in mice. In contrast to exhausted CD39+ T cells in chronic infection, CD39+ TRM are fully functional when stimulated ex vivo with cognate antigen. This work further expands the identity of CD39 beyond a T cell exhaustion marker.

immunology↗

bioRxiv2021

Therapeutic activation of virus-specific resident memory T cells within the glioblastoma microenvironment

Glioblastoma multiforme (GBM) is among the most aggressive, treatment resistant cancers, and despite standard of care surgery, radiation and chemotherapy, is invariably fatal. GBM is marked by local and systemic immunosuppression, contributing to resistance to existing immunotherapies that have had success in other tumor types. Memory T cells specific for previous infections reside in tissues throughout the host and these tissue resident memory T cells (TRM) are capable of rapid and potent immune activation. Here, we show that virus-specific memory CD8+ T cells expressing tissue resident markers populate the mouse and human glioblastoma microenvironment. Reactivating virus-specific TRM through intra-tumoral delivery of adjuvant-free virus-derived peptide triggered local immune activation. This delivery translated to anti-neoplastic effects, which improved survival in a murine glioblastoma model. Our results indicate that virus-specific TRM are a significant part of the glioblastoma immune microenvironment and can be leveraged to promote anti-tumoral immunity.

immunology↗

bioRxiv2019

Critical role for Slam/SAP signaling in the thymic developmental programming of IL-17- and IFN-γ-producing γδ T cells

During thymic development, {gamma}{delta} T cells commit to either an IFN-{gamma}- or an IL-17-producing phenotype through mechanisms that remain unclear. Here, we investigated whether the SLAM/SAP signaling pathway played a role in the functional programming of thymic {gamma}{delta} T cells. Characterization of SLAM family receptor expression revealed that thymic {gamma}{delta} T cell subsets were each marked by distinct co-expression profiles of SLAMF1, SLAMF4, and SLAMF6. In the thymus, immature CD24hi V{gamma}1 and V{gamma}4 {gamma}{delta} T cells were largely contained within a SLAMF1+SLAMF6+ double positive (DP) population, while mature CD24low subsets were either SLAMF1+ or SLAMF6+ single positive (SP) cells. In the periphery, SLAMF1 and SLAMF6 expression on V{gamma}1, V{gamma}4, and V{gamma}6 T cells distinguished IL-17- and IFN-{gamma}-producing subsets, respectively. Disruption of SLAM family receptor signaling through deletion of SAP resulted in impaired thymic {gamma}{delta} T cell maturation at the CD24hiSLAMF1+SLAMF6+ DP stage that was associated with a decreased frequency of CD44+ROR{gamma}t+ {gamma}{delta} T cells. These defects were in turn associated with impaired {gamma}{delta} T cell IL-17 and IFN-{gamma} production in both the thymus as well as in peripheral tissues. The role for SAP was subset-specific, as V{gamma}1, V{gamma}4, V{gamma}5, but not V{gamma}6 subsets were SAP-dependent. Together, these data suggest that the SLAM/SAP signaling pathway regulates a critical checkpoint in the functional programming of IL-17 and IFN-{gamma}-producing {gamma}{delta} T cell subsets during thymic development.

immunology↗