Tolerance induction in memory CD4 T cells is partial and reversible

Gray, J. I. et al. (2021) Tolerance induction in memory CD4 T cells is partial and reversible. Immunology, 162(1), pp. 68-83. (doi: 10.1111/imm.13263) (PMID:32931017) (PMCID:PMC7730012)

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Abstract

Memory T cells respond rapidly in part because they are less reliant on heightened levels of costimulatory molecules. This enables rapid control of secondary infecting pathogens but presents challenges to efforts to control or silence memory CD4 T cells, for example in antigen specific tolerance strategies for autoimmunity. We have examined the transcriptional and functional consequences of re‐activating memory CD4 T cells in the absence of an adjuvant. We find that memory CD4 T cells generated by infection or immunisation survive secondary activation with antigen delivered without adjuvant, regardless of their location in secondary lymphoid organs or peripheral tissues. These cells were, however, functionally altered following a tertiary immunisation with antigen and adjuvant, proliferating poorly but maintaining their ability to produce inflammatory cytokines. Transcriptional and cell cycle analysis of these memory CD4 T cells suggest they are unable to commit fully to cell division potentially because of low expression of DNA repair enzymes. In contrast, these memory CD4 T cells could proliferate following tertiary reactivation by viral re‐infection. These data indicate that antigen specific tolerogenic strategies must examine multiple parameters of T cell function, and provide insight into the molecular mechanisms that may lead to deletional tolerance of memory CD4 T cells.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Garside, Professor Paul and Al-Khabouri, Ms Shaima and Macleod, Dr Megan and Otto, Dr Thomas and Gray, Joshua and Morton, Mr Fraser
Authors: Gray, J. I., Al-Khabouri, S., Morton, F., Clambey, E. T., Gapin, L., Matsuda, J. L., Kappler, J. W., Marrack, P., Garside, P., Otto, T. D., and MacLeod, M. K.L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Immunology
Publisher:Wiley
ISSN:0019-2805
ISSN (Online):1365-2567
Published Online:15 September 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Immunology 162(1): 68-83
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
166803Molecular requirements for the induction of tolerance in activated and memory CD4 T cells.Megan MacLeodVersus Arthritis (ARTRESUK)3628/MP/19905Institute of Infection, Immunity & Inflammation
190394MRC Doctoral Training Grant 2011-2015Mary Beth KneafseyMedical Research Council (MRC)MR/J50032X/1Research and Innovation Services