Chimeric antigen receptors (CARs) have shown remarkable ability to re-direct T cells to target CD19-expressing tumours, resulting in remission rates of up to 90% in individuals with paediatric acute lymphoblastic lymphoma. Lessons learned from these clinical trials of adoptive T cell therapy for cancer, as well as investments made in manufacturing T cells at commercial scale, have inspired researchers to develop CARs for additional applications. Here, we explore the challenges and opportunities of using this technology to target infectious diseases such as with HIV and undesired immune responses such as autoimmunity and transplant rejection. Despite substantial obstacles, the potential of CAR T cells to enable cures for a wide array of disease settings could be transformational for the medical field.
Summary Mutations in PINK1, a serine/threonine kinase linked to familial early onset Parkinsonism, compromise mitochondrial integrity and metabolism and impair AKT signaling. As the activation of a naïve T cell requires an AKT-dependent reorganization of a cell’s metabolic machinery, we sought to determine if PINK1 deficient T cells lack the ability to undergo activation and differentiation. We show that CD4+ T cells from PINK1 knockout mice fail to properly phosphorylate AKT upon activation, resulting in reduced expression of the IL-2 receptor subunit CD25. Following, deficient IL-2 signaling mutes the activation-induced increase in respiratory capacity and mitochondrial membrane potential. Under polarization conditions favoring the development of induced regulatory T cells, PINK1−/− T cells exhibit a reduced ability to suppress bystander T cell proliferation despite normal FoxP3 expression kinetics. Our results describe a critical role for PINK1 in integrating extra-cellular signals with metabolic state during T cell fate determination, and may have implications for the understanding of altered T cell populations and immunity during the progression of active Parkinson’s disease or other immunopathologies.
BackgroundNociceptive and neuropathic pain occurs as part of the disease process after traumatic brain injury (TBI) in humans. Central and peripheral inflammation, a major secondary injury process initiated by the traumatic brain injury event, has been implicated in the potentiation of peripheral nociceptive pain. We hypothesized that the inflammatory response to diffuse traumatic brain injury potentiates persistent pain through prolonged immune dysregulation.ResultsTo test this, adult, male C57BL/6 mice were subjected to midline fluid percussion brain injury or to sham procedure. One cohort of mice was analyzed for inflammation-related cytokine levels in cortical biopsies and serum along an acute time course. In a second cohort, peripheral inflammation was induced seven days after surgery/injury with an intraplantar injection of carrageenan. This was followed by measurement of mechanical hyperalgesia, glial fibrillary acidic protein and Iba1 immunohistochemical analysis of neuroinflammation in the brain, and flow cytometric analysis of T-cell differentiation in mucosal lymph. Traumatic brain injury increased interleukin-6 and chemokine ligand 1 levels in the cortex and serum that peaked within 1–9 h and then resolved. Intraplantar carrageenan produced mechanical hyperalgesia that was potentiated by traumatic brain injury. Further, mucosal T cells from brain-injured mice showed a distinct deficiency in the ability to differentiate into inflammation-suppressing regulatory T cells (Tregs).ConclusionsWe conclude that traumatic brain injury increased the inflammatory pain associated with cutaneous inflammation by contributing to systemic immune dysregulation. Regulatory T cells are immune suppressors and failure of T cells to differentiate into regulatory T cells leads to unregulated cytokine production which may contribute to the potentiation of peripheral pain through the excitation of peripheral sensory neurons. In addition, regulatory T cells are identified as a potential target for therapeutic rebalancing of peripheral immune homeostasis to improve functional outcome and decrease the incidence of peripheral inflammatory pain following traumatic brain injury.
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