TCR signaling via NFATc1 constrains IL-15-induced NK-like activation of human memory CD8+ T cells

Lee, H.; Kim, S.-Y.; Kim, S.-H.; Yu, H.; Jeong, S.; Kim, K. H.; Kim, C. G.; Koh, J.-Y.; Kim, H.-D.; Han, J. W.; Park, S.-H.; Eun, H. S.; Shin, E.-C.

doi:10.1101/2025.01.13.632884

bioRxiv · 10.1101/2025.01.13.632884

TCR signaling via NFATc1 constrains IL-15-induced NK-like activation of human memory CD8+ T cells

Lee, H.·Kim, S.-Y.·Kim, S.-H.·Yu, H.·Jeong, S.·Kim, K. H.·Kim, C. G.·Koh, J.-Y.·Kim, H.-D.·Han, J. W.·Park, S.-H.·Eun, H. S.·Shin, E.-C.

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Abstract

Here we investigated the regulatory mechanisms of TCR-independent bystander activation and NK-like cytotoxicity of human memory CD8+ T cells. We found that TCR signals suppressed characteristic features of IL-15-induced CD8+ T-cell activation, including increased NKG2D expression and upregulation of genes related to NK cytotoxicity and IFN response. Moreover, ionomycin suppressed IL-15-induced bystander activation and NK-like cytotoxicity, indicating that Ca2+-calcineurin signaling is responsible for TCR-mediated suppression of IL-15-induced bystander activation. In detail, NFATc1 suppressed IL-15-induced bystander activation via binding to AP-1 that is necessary for the IL-15-induced upregulation of NK cytotoxicity-related genes. Consistent with these results, calcineurin inhibitors enhanced IL-15-induced NKG2D expression in the presence of TCR signals. Additionally, we defined genes upregulated by IL-15 and downregulated by concurrent TCR signals as an IL-15-induced bystander activation gene set, and found that this gene signature was upregulated in bystander CD8+ T cells from patients with hepatitis A virus infection. This study paves the way for further investigation of bystander CD8+ T-cell activation in various pathological conditions, and its regulation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=191 HEIGHT=200 SRC="FIGDIR/small/632884v2_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@1e6c320org.highwire.dtl.DTLVardef@114a23eorg.highwire.dtl.DTLVardef@1a7b9edorg.highwire.dtl.DTLVardef@9faccc_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LITCR signaling downregulates IL-15-induced transcriptomic features related to NK-like bystander activation of human memory CD8+ T cells via the Ca2+-calcineurin pathway. C_LIO_LINFATc1 suppresses IL-15-induced bystander activation via binding to AP-1, which is responsible for IL-15-induced NK-like cytotoxic activity. C_LIO_LICalcineurin inhibitors cannot suppress IL-15-induced bystander CD8+ T-cell activation, and paradoxically increase IL-15-induced NKG2D expression in the presence of TCR signals. C_LIO_LIGenes upregulated by IL-15 and downregulated by concurrent TCR signals define the gene set of bystander CD8+ T-cell activation, which was validated in disease contexts. C_LI

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Lee, H., Kim, S.-Y., Kim, S.-H., Yu, H., Jeong, S., Kim, K. H., Kim, C. G., Koh, J.-Y., Kim, H.-D., Han, J. W., Park, S.-H., Eun, H. S., Shin, E.-C.. 2025-01-15. TCR signaling via NFATc1 constrains IL-15-induced NK-like activation of human memory CD8+ T cells. https://doi.org/10.1101/2025.01.13.632884

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