Memory CD8 T cells are vulnerable to chronic IFN-γ signals but not to CD4 T cell deficiency in MHCII-deficient mice

Ruka Setoguchi (), Tomoya Sengiku, Hiroki Kono, Eiryo Kawakami, Masato Kubo, Tadashi Yamamoto and Shohei Hori
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Ruka Setoguchi: RIKEN Center for Integrative Medical Sciences
Tomoya Sengiku: The University of Tokyo
Hiroki Kono: The University of Tokyo
Eiryo Kawakami: RIKEN Information R&D and Strategy Headquarters, RIKEN
Masato Kubo: Tokyo University of Science
Tadashi Yamamoto: RIKEN Center for Integrative Medical Sciences
Shohei Hori: The University of Tokyo

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract The mechanisms by which the number of memory CD8 T cells is stably maintained remains incompletely understood. It has been postulated that maintaining them requires help from CD4 T cells, because adoptively transferred memory CD8 T cells persist poorly in MHC class II (MHCII)-deficient mice. Here we show that chronic interferon-γ signals, not CD4 T cell-deficiency, are responsible for their attrition in MHCII-deficient environments. Excess IFN-γ is produced primarily by endogenous colonic CD8 T cells in MHCII-deficient mice. IFN-γ neutralization restores the number of memory CD8 T cells in MHCII-deficient mice, whereas repeated IFN-γ administration or transduction of a gain-of-function STAT1 mutant reduces their number in wild-type mice. CD127high memory cells proliferate actively in response to IFN-γ signals, but are more susceptible to attrition than CD127low terminally differentiated effector memory cells. Furthermore, single-cell RNA-sequencing of memory CD8 T cells reveals proliferating cells that resemble short-lived, terminal effector cells and documents global downregulation of gene signatures of long-lived memory cells in MHCII-deficient environments. We propose that chronic IFN-γ signals deplete memory CD8 T cells by compromising their long-term survival and by diverting self-renewing CD127high cells toward terminal differentiation.

Date: 2024
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DOI: 10.1038/s41467-024-48704-4

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