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| Item Type: | Article |
|---|---|
| Title: | The AICL-KLRF1 axis supports CD4-CD8 T cell communication and cytokine competence in pre-exhausted CD8(+) T cells |
| Creators: |
Barone, Matthias  ORCID: https://orcid.org/0000-0002-6554-6464, Peidli, Stefan ORCID: https://orcid.org/0000-0002-4257-8690, Neuschulz, Anika ORCID: https://orcid.org/0000-0001-6163-3344, Riesterer, Karla, Iwert, Christina, Junquera, Laia ORCID: https://orcid.org/0009-0006-9259-0213, Sai, Somesh ORCID: https://orcid.org/0000-0001-6865-341X, Bolaji, Olufemi, Bakoueva, Diana, Appelt, Christine ORCID: https://orcid.org/0009-0000-7865-9911, Obermayer, Benedikt ORCID: https://orcid.org/0000-0002-9116-630X, Klinger, Bertram ORCID: https://orcid.org/0000-0003-0242-1506, Trinks, Alexandra ORCID: https://orcid.org/0000-0001-9983-1506, Sieber, Anja ORCID: https://orcid.org/0000-0001-6588-8547, Blüthgen, Nils ORCID: https://orcid.org/0000-0002-0171-7447 and Sawitzki, Birgit ORCID: https://orcid.org/0000-0001-8166-8579
|
| Abstract: | Memory-like or precursor exhausted (Tpex) CD8(+) T cells are a critical reservoir in chronic infections and cancer, yet the signals sustaining their cytokine production remain unclear. Here, we identify KLRF1 as part of a CD4-CD8 communication axis that supports cytokine production in late-differentiated human CD8(+) T cells. KLRF1 is upregulated in late-differentiated CD8(+) T cells, and neutralizing KLRF1 reduces TNF and IFN-γ production. Differentiated CD4(+) T cells express the KLRF1 ligand AICL, and in co-culture only AICL(+) - not AICL(-) - CD4(+) T cells enhance cytokine output in CD8(+) T cells. Using spatial proteomics of lung adenocarcinoma and adjacent tissue, we found that CD4(+) AICL(+) and CD8(+) KLRF1(+) T cells are enriched and spatially interacting in non-tumor regions, whereas both populations are reduced within tumor tissue. Single-cell RNA-seq of tissue samples and scRNA/ATAC analyses of circulating immune cells further showed that CD8(+)KLRF1(+) T cells display a Tpex-like transcriptional and chromatin-accessibility profile. Together, these data identify the AICL-KLRF1 axis as a CD4(+)-CD8(+) communication pathway that supports cytokine competence in late-differentiated CD8(+) T cells. |
| Keywords: | Cytotoxic T Cell, KLRF1, T Cell Exhaustion, Tumor Immunology |
| Source: | EMBO Reports |
| ISSN: | 1469-221X |
| Publisher: | Springer Nature / EMBO Press |
| Volume: | 27 |
| Number: | 8 |
| Page Range: | 2029-2060 |
| Date: | 27 April 2026 |
| Official Publication: | https://doi.org/10.1038/s44319-026-00732-5 |
| PubMed: | View item in PubMed |
| Related to: |
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