Biology subjects

Pease, L. R.

Publications and source records attributed to Pease, L. R..

3 recordsLinked to original sources

bioRxiv2025

T cells use TNF and IFNγ for paracrine killing with target discrimination programmed by pathogen-derived factors

Cytotoxic T lymphocytes (CTLs) are known to eliminate target cells through perforin-mediated, contact-dependent killing - a process limited by the number of effector T cells despite its serial nature. CTLs likely also possess a mass killing mechanism that can eliminate target cells more efficiently. Using CAR-T cells against B7H3 present on B16 tumor targets, we demonstrate that activated T cells can also kill targets in a perforin-independent manner by releasing diffusible TNF and IFN{gamma} capable of killing nearby targets in a paracrine fashion even if they bear no antigen. Against an unperturbed target, paracrine killing is inefficient but is enhanced by the deletion of TNFR1 signaling molecules such as TAK1, HOIP, or TBK1/IKK{varepsilon}. Notably, these molecules are inhibited naturally by pathogen-encoded antagonists. Expression of a microbial-encoded antagonist, such as the Yersinia-encoded YopJ that antagonizes TAK1 or Ebola-encoded VP35 that antagonizes TBK1/IKK{varepsilon}, alters the target cell response to these cytokines from non-lethal to lethal. We propose that target cells are inherently resistant to killing by TNF and IFN{gamma}, but the presence of a microbial factor alters this sensitivity, providing for the selective elimination of the infected cell while minimizing harm to uninfected bystander cells. We propose the term pathogen-restriction to describe this discriminatory mechanism. Potentially, any microbial-derived factor that crosstalks with the TNF and IFN{gamma} signaling pathways can function as a pathogen-restriction element. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/696308v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@ea6418org.highwire.dtl.DTLVardef@517489org.highwire.dtl.DTLVardef@1ba0e22org.highwire.dtl.DTLVardef@1f5fef8_HPS_FORMAT_FIGEXP M_FIG C_FIG Short SummaryT cells use TNF and IFN{gamma} to kill target cells in a paracrine manner where target elimination is restricted by the presence of pathogen-derived factors.

immunology↗

bioRxiv2024

PP2A catalytic subunit alpha is critically required for CD8+ T cell homeostasis and anti-bacterial responses

While the functions of tyrosine phosphatases in T cell biology have been extensively studied, our knowledge on the contribution of serine/threonine phosphatases in T cells remains poor. Protein phosphatase 2A (PP2A) is one of the most abundantly expressed serine/threonine phosphatases. It is important in thymocyte development and CD4+ T cell differentiation. Utilizing a genetic model in which its catalytic subunit alpha isoform (PP2A C) is deleted in T cells, we investigated its contribution to CD8+ T cell homeostasis and effector functions. Our results demonstrate that T cell intrinsic PP2A C is critically required for CD8+ T cell homeostasis in secondary lymphoid organs and intestinal mucosal site. Importantly, PP2A C deficient CD8+ T cells exhibit reduced proliferation and survival. CD8+ T cell anti-bacterial response is strictly dependent on PP2A C. Expression of Bcl2 transgene rescues CD8+ T cell homeostasis in spleens, but not in intestinal mucosal site, nor does it restore the defective anti-bacterial responses. Finally, proteomics and phosphoproteomics analyses reveal potential targets dependent on PP2A C, including mTORC1 and AKT. Thus, PP2A C is a key modulator of CD8+ T cell homeostasis and effector functions.

immunology↗

bioRxiv2020

Severe and multifaceted systemic immunosuppression caused by experimental cancers of the central nervous system requires release of non-steroid soluble mediators

Immunosuppression of unknown etiology is a hallmark feature of glioblastoma (GBM) and is characterized by decreased CD4 T cell counts and down regulation of MHC class II expression on peripheral blood monocytes in patients. This immunosuppression is a critical barrier to the successful development of immunotherapies for GBM. We recapitulated the immunosuppression observed in GBM patients in the C57BL/6 mouse and investigated the etiology of low CD4 T cell counts. We determined that thymic involution was a hallmark feature of immunosuppression in three distinct models of CNS cancer, including mice harboring GL261 glioma, B16 melanoma, and in a spontaneous model of Diffuse Intrinsic Pontine Glioma (DIPG). In addition to thymic involution, we determined that tumor growth in the brain induced significant splenic involution, reductions in peripheral T cells, reduced MHC class II expression on hematopoietic cells, and a modest increase in bone marrow resident CD4 T cells with a naive phenotype. Using parabiosis we report that thymic involution, declines in peripheral T cell counts, and reduced MHC class II expression levels were mediated through circulating blood-derived factors. Conversely, T cell sequestration in the bone marrow was not governed through circulating factors. Serum isolated from glioma-bearing mice potently inhibited proliferation and functions of T cells both in vitro and in vivo. Interestingly, the factor responsible for immunosuppression in serum is nonsteroidal and of high molecular weight. Through further analysis of neurological disease models, we determined that the aforementioned immunosuppression was not unique to cancer itself, but rather occurs in response to CNS injury. Noncancerous acute neurological insults also induced significant thymic involution and rendered serum immunosuppressive. Both thymic involution and serum-derived immunosuppression were reversible upon clearance of brain insults. These findings demonstrate that CNS cancers cause multifaceted immunosuppression and pinpoint circulating factors as a target of intervention to restore immunity. Short SummaryCNS cancers and other brain-injuries suppress immunity through release of non-steroid soluble factors that disrupt immune homeostasis and dampen responses of the peripheral immune system. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/006825v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@14e90c2org.highwire.dtl.DTLVardef@101de5corg.highwire.dtl.DTLVardef@1ad8534org.highwire.dtl.DTLVardef@1041fef_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

immunology↗