Browsing by Subject "Immune dysfunction"

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    Aging- and Tumor-Mediated Increase in CD8+CD28- T Cells Might Impose a Strong Barrier to Success of Immunotherapy in Glioblastoma
    (American Association of Immunologists, 2021-06-08) Huff, Wei X.; Bam, Marpe; Shireman, Jack M.; Kwon, Jae Hyun; Song, Leo; Newman, Sharlé; Cohen-Gadol, Aaron A.; Shapiro, Scott; Jones, Tamara; Fulton, Kelsey; Liu, Sheng; Tanaka, Hiromi; Liu, Yunlong; Wan, Jun; Dey, Mahua; Neurological Surgery, School of Medicine
    Clinical use of various forms of immunotherapeutic drugs in glioblastoma (GBM), has highlighted severe T-cell dysfunction such as exhaustion in GBM patients. However, reversing T-cell exhaustion using immune checkpoint inhibitors in GBM clinical trials has not shown significant overall survival benefit. Phenotypically, CD8+ T cells with downregulated CD28 co-receptors, low CD27 expression, increased CD57 expression, and telomere shortening, are classified as senescent T cells. These senescent T cells are normally seen as part of aging and also in many forms of solid cancers. Absence of CD28 on T-cells leads to several functional irregularities including reduced TCR diversity, incomplete activation of T cells, and defects in antigen induced proliferation. In the context of GBM, presence and/or function of these CD8+CD28− T-cells is unknown. In this clinical correlative study, we investigated the effect of aging as well as tumor microenvironment on CD8+ T-cell phenotype as an indicator of its function in GBM patients. We systematically analyzed and describe a large population of CD8+CD28− T-cells in both the blood and tumor infiltrating lymphocytes of GBM patients. We found that phenotypically these CD8+CD28− T-cells represent a distinct population compared to exhausted T-cells. Comparative transcriptomic and pathway analysis of CD8+CD28− T cell populations in GBM patients revealed that tumor microenvironment might be influencing several immune related pathways and thus further exaggerating the age associated immune dysfunction in this patient population.
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    Repeated Mild Traumatic Brain Injury in Mice Elicits Long Term Innate Immune Cell Alterations in Blood, Spleen, and Brain
    (Elsevier, 2023) Smith, Jared A.; Nguyen, Tyler; Karnik, Sonali; Davis, Brittany C.; Al-Juboori, Mohammed H.; Kacena, Melissa A.; Obukhov, Alexander G.; White, Fletcher A.; Anesthesia, School of Medicine
    Mild traumatic brain injury is an insidious event whereby the initial injury leads to ongoing secondary neuro- and systemic inflammation through various cellular pathways lasting days to months after injury. Here, we investigated the impact of repeated mild traumatic brain injury (rmTBI) and the resultant systemic immune response in male C57B6 mice using flow cytometric methodology on white blood cells (WBCs) derived from the blood and spleen. Isolated mRNA derived from spleens and brains of rmTBI mice was assayed for changes in gene expression at one day, one week, and one month following the injury paradigm. We observed increases in Ly6C+, Ly6C-, and total monocyte percentages in both blood and spleen at one month after rmTBI. Differential gene expression analysis for the brain and spleen tissues uncovered significant changes in many genes, including csf1r, itgam, cd99, jak1,cd3ε, tnfaip6, and nfil3. Additional analysis revealed alterations in several immune signaling pathways over the course of one month in the brain and spleen of rmTBI mice. Together, these results indicate that rmTBI produces pronounced gene expression changes in the brain and spleen. Furthermore, our data suggest that monocyte populations may reprogram towards the proinflammatory phenotype over extended periods of time after rmTBI.