Activated T cell [Neurosurgery Wiki]

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====== Activated T cell ======

[[T-cell]] activation is a key event in the adaptive [[immune response]] and is vital to the generation of both cellular and humoral [[immunity]]. Activation is required not only for effective [[CD4]] T cell responses but also to provide help for [[B cell]]s and the generation of cytotoxic T cell responses.

Activated [[T cell]]s must still traffic to, infiltrate, and persist within the [[tumor]] in order to mediate tumor [[lysis]]. These [[requirement]]s for [[efficacy]] pose unique challenges for brain tumor [[immunotherapy]], due to specific anatomical barriers and populations of specialized [[immune cell]]s within the central nervous system that function to constrain [[immunity]]. Both [[autoimmune]] and [[infectious disease]]s of the central nervous system provide a wealth of information on how T cells can successfully migrate to the central nervous system and then engender sustained immune responses
((Congdon KL, Sanchez-Perez LA, Sampson JH. Effective Effectors: How T cells
Access and Infiltrate the Central nervous System. Pharmacol Ther. 2018 Dec 14.
pii: S0163-7258(18)30229-8. doi: 10.1016/j.pharmthera.2018.12.007. [Epub ahead of
print] Review. PubMed PMID: 30557632.
)).
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An activated [[T cell]] (ATC) [[protocol]] including [[cytokine]] activation and expansion in culture to target [[glioma stem cell]] (GSC) were generated and optimized for a planned phase I [[clinical trial]]. Miyaguchi et al compared three different [[antigen]]-loading methods on [[dendritic cell]]s (DCs) to effectively activate T cells, which were GBM patient-derived [[glioma stem cell]] (GSC)-[[lysate]], acid-eluate of GSCs, and synthetic peptides derived from [[protein]]s expressed in GSCs. DCs derived from HLA-A2 positive [[blood]] samples were loaded with tumor-associated antigens (TAAs). [[Autologous]] T cells were activated by co-culturing with loaded DCs. The [[efficiency]] and [[cytotoxicity]] of ATCs were evaluated by targeting TAA-pulsed DCs or T2 cells, GSCs, or autologous [[PHA blast]]s. Characteristics of ATCs were evaluated by [[Flow Cytometry]] and ELISpot assay, which showed an increased number of ATCs secreting IFN-γ targeting GSCs as compared with non-activated T cells and unloaded target cells. Neither GSC-lysate nor acid-eluate loading showed enhancement in response to ATCs but the synthetic peptide pool showed significantly increased IFN-γ secretion and increased cytotoxicity towards target cells. These results demonstrate that ATCs activated using a TAA synthetic peptide pool efficiently enhance cytotoxicity specifically to target cells including GSC
((Miyaguchi K, Wang H, Black KL, Shiao SL, Wang R, Yu JS. Activated T cell therapy targeting glioblastoma cancer stem cells. Sci Rep. 2023 Jan 5;13(1):196. doi: 10.1038/s41598-022-27184-w. PMID: 36604465.)).

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Data indicate that the leptomeninges represent a checkpoint at which activated T cells are licensed to enter the CNS parenchyma and non-activated T cells are preferentially released into the CSF, from where they can reach areas of antigen availability and tissue damage
((Schläger C, Körner H, Krueger M, Vidoli S, Haberl M, Mielke D, Brylla E,
Issekutz T, Cabañas C, Nelson PJ, Ziemssen T, Rohde V, Bechmann I, Lodygin D,
Odoardi F, Flügel A. Effector T-cell trafficking between the leptomeninges and
the cerebrospinal fluid. Nature. 2016 Feb 18;530(7590):349-53. doi:
10.1038/nature16939. Epub 2016 Feb 10. PubMed PMID: 26863192.)).

Global T cell deficiency exacerbates motor behavioral defects in a rat model of [[Parkinson's disease]]
((Wheeler CJ, Seksenyan A, Koronyo Y, Rentsendorj A, Sarayba D, Wu H, Gragg A,
Siegel E, Thomas D, Espinosa A, Thompson K, Black K, Koronyo-Hamaoui M, Pechnick 
R, Irvin DK. T-Lymphocyte Deficiency Exacerbates Behavioral Deficits in the
6-OHDA Unilateral Lesion Rat Model for Parkinson's Disease. J Neurol
Neurophysiol. 2014 May;5(3). pii: 209. PubMed PMID: 25346865.)).