Functional impairment of "helpless" CD8+ memory T cells is transient and driven by prolonged but finite cognate antigen presentation

van der Heide, V.; Davenport, B.; Cubitt, B.; Roudko, V.; Choo, D.; Humblin, E.; Jhun, K.; Angeliadis, K.; Dawson, T.; Furtado, G.; Kamphorst, A. O.; Ahmed, R.; de la Torre, J. C.; Homann, D.

doi:10.1101/2024.01.22.576725

bioRxiv · 10.1101/2024.01.22.576725

Functional impairment of "helpless" CD8+ memory T cells is transient and driven by prolonged but finite cognate antigen presentation

van der Heide, V.·Davenport, B.·Cubitt, B.·Roudko, V.·Choo, D.·Humblin, E.·Jhun, K.·Angeliadis, K.·Dawson, T.·Furtado, G.·Kamphorst, A. O.·Ahmed, R.·de la Torre, J. C.·Homann, D.

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Abstract

Generation of functional CD8+ T cell memory typically requires engagement of CD4+ T cells. However, in certain scenarios, such as acutely-resolving viral infections, effector (TE) and subsequent memory (TM) CD8+ T cell formation appear impervious to a lack of CD4+ T cell help during priming. Nonetheless, such "helpless" CD8+ TM respond poorly to pathogen rechallenge. At present, the origin and long-term evolution of helpless CD8+ T cell memory remain incompletely understood. Here, we demonstrate that helpless CD8+ TE differentiation is largely normal but a multiplicity of helpless CD8 TM defects, consistent with impaired memory maturation, emerge as a consequence of prolonged yet finite exposure to cognate antigen. Importantly, these defects resolve over time leading to full restoration of CD8+ TM potential and recall capacity. Our findings provide a unified explanation for helpless CD8+ T cell memory and emphasize an unexpected CD8+ TM plasticity with implications for vaccination strategies and beyond.

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van der Heide, V., Davenport, B., Cubitt, B., Roudko, V., Choo, D., Humblin, E., Jhun, K., Angeliadis, K., Dawson, T., Furtado, G., Kamphorst, A. O., Ahmed, R., de la Torre, J. C., Homann, D.. 2024-01-26. Functional impairment of "helpless" CD8+ memory T cells is transient and driven by prolonged but finite cognate antigen presentation. https://doi.org/10.1101/2024.01.22.576725

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