Regulation of temporal cytokine production by co-stimulation receptors in TCR-T cells is lost in CAR-T cells.

Autor:	Patel A; The Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK., Kutuzov MA; The Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK., Dustin ML; The Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, UK., van der Merwe PA; The Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK., Dushek O; The Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
Jazyk:	angličtina
Zdroj:	Immunotherapy advances [Immunother Adv] 2024 Jun 19; Vol. 4 (1), pp. ltae004. Date of Electronic Publication: 2024 Jun 19 (Print Publication: 2024).
DOI:	10.1093/immadv/ltae004
Abstrakt:	CD8+ T cells contribute to immune responses by producing cytokines when their T-cell receptors (TCRs) recognise peptide antigens on major-histocompability-complex class I. However, excessive cytokine production can be harmful. For example, cytokine release syndrome is a common toxicity observed in treatments that activate T cells, including chimeric antigen receptor (CAR)-T-cell therapy. While the engagement of costimulatory receptors is well known to enhance cytokine production, we have limited knowledge of their ability to regulate the kinetics of cytokine production by CAR-T cells. Here we compare early (0-12 h) and late (12-20 h) production of IFN-gg, IL-2, and TNF-a production by T cells stimulated via TCR or CARs in the presence or absence ligands for CD2, LFA-1, CD28, CD27, and 4-1BB. For T cells expressing TCRs and 1st-generation CARs, activation by antigen alone was sufficient to stimulate early cytokine production, while co-stimulation by CD2 and 4-1BB was required to maintain late cytokine production. In contrast, T cells expressing 2nd-generation CARs, which have intrinsic costimulatory signalling motifs, produce high levels of cytokines in both early and late periods in the absence of costimulatory receptor ligands. Losing the requirement for costimulation for sustained cytokine production may contribute to the effectiveness and/or toxicity of 2nd-generation CAR-T-cell therapy. Competing Interests: Omer Dushek and P. Anton van der Merwe have financial interests MatchBio Ltd. (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology.)
Databáze:	MEDLINE
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