School of Infection & Immunity

Institute of Infection, Immunity and Inflammation PhD student Josh Gray has seen his research on tolerance induction in memory CD4 T cells published by the journal Immunology.

Memory CD4 T cells can act more quickly and effectively upon a second encounter with the same pathogen, providing enhanced protection.

However, CD4 T cells sometimes respond to innocuous stimuli such as substances in our environment or our own cells.

These responses can lead to allergies and autoimmunity, reducing the quality and, in some cases, life span of affected individuals. In these cases, the improved responses of memory CD4 T cells are dangerous.

Josh wanted to know what happens to memory CD4 T cells when they are exposed to signals that are known to be able to turn off naïve CD4 T cells that haven’t been previously activated.

This is important because trials are underway using such signals to treat people with allergies and autoimmune disease.

He found that unlike naïve CD4 T cells, the memory CD4 T cells exposed to ‘off’ signals survived and could respond to subsequent activation signals.

However, these subsequent responses were reduced and the memory CD4 T cells underwent an unusual form of cell death by a process called mitotic catastrophe.

In this process, the cells begin to divide but fail to correctly undergo mitosis – our data suggest this is because the cells failed to upregulate the molecules required to check the newly replicated DNA.

Together these data suggest that memory CD4 T cells that co-ordinate diseases like allergy and autoimmunity could be turned off with these ‘off’ signals.

However, when researchers reactivated memory CD4 T cells exposed to ‘off’ signals with more inflammatory signals by stimulating them with a virus, the cells could respond normally. These data suggest that the memory CD4 T cells exposed to ‘off’ signals are not permanently silenced.

Overall, the study suggests that there is a need to carefully monitor pathogenic CD4 T cells exposed to ‘off’ signals to check whether they will respond to further activation by dying or surviving and causing more damage.

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Tolerance induction in memory CD4 T cells is partial and reversible

• Joshua I. Gray, Shaima Al‐Khabouri, Fraser Morton, Eric T. Clambey, Laurent Gapin, Jennifer L. Matsuda, John W. Kappler, Philippa Marrack, Paul Garside, Thomas D. Otto, Megan K.L. MacLeod
• First published: 15 September 2020 https://doi.org/10.1111/imm.13263

Author Contribution

Joshua I. Gray designed and performed experiments, analysed data and wrote the manuscript; Thomas D. Otto and Shaima Al‐Khabouri analysed data; Fraser Morton, Eric T. Clambey, Laurent Gapin, Jennifer L. Matsuda, John W. Kappler and Philippa Marrack designed and produced essential tools; Paul Garside designed experiments; Megan K. L. MacLeod designed and performed the research, analysed data and wrote the manuscript. All authors approved the manuscript.

First published: 9 November 2020