The alarmin interleukin-33 promotes the expansion and preserves the stemness of Tcf-1+ CD8+ T cells in chronic viral infection

T cell factor 1 (Tcf-1) expressing CD8+ T cells exhibit stem-like self-renewing capacity, rendering them key for immune defense against chronic viral infection and cancer. Yet, the signals that promote the formation and maintenance of these stem-like CD8+ T cells (CD8+SL) remain poorly defined. Stud...

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Published in:	Immunity (Cambridge, Mass.) Vol. 56; no. 4; pp. 813 - 828.e10
Main Authors:	Marx, Anna-Friederike, Kallert, Sandra M., Brunner, Tobias M., Villegas, José A., Geier, Florian, Fixemer, Jonas, Abreu-Mota, Tiago, Reuther, Peter, Bonilla, Weldy V., Fadejeva, Jelizaveta, Kreutzfeldt, Mario, Wagner, Ingrid, Aparicio-Domingo, Patricia, Scarpellino, Leo, Charmoy, Mélanie, Utzschneider, Daniel T., Hagedorn, Claudia, Lu, Min, Cornille, Karen, Stauffer, Karsten, Kreppel, Florian, Merkler, Doron, Zehn, Dietmar, Held, Werner, Luther, Sanjiv A., Löhning, Max, Pinschewer, Daniel D.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 11-04-2023
Subjects:	Alarmins - metabolism Animals CD8+SL CD8-Positive T-Lymphocytes chronic viral infection IL-33 Interleukin-1 Receptor-Like 1 Protein - metabolism interleukin-33 Interleukin-33 - metabolism Lymphocytic Choriomeningitis - immunology Lymphocytic choriomeningitis virus Mice Mice, Inbred C57BL Persistent Infection stem-like CD8+ T cells T cell factor 1 T Cell Transcription Factor 1 - metabolism Tcf-1 type I interferon CD8+SL type I interferon chronic viral infection Tcf-1 stem-like CD8+ T cells T cell factor 1 lymphocytic choriomeningitis virus interleukin-33 IL-33 stem-like CD8(+) T cells CD8(+)SL
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Summary:	T cell factor 1 (Tcf-1) expressing CD8+ T cells exhibit stem-like self-renewing capacity, rendering them key for immune defense against chronic viral infection and cancer. Yet, the signals that promote the formation and maintenance of these stem-like CD8+ T cells (CD8+SL) remain poorly defined. Studying CD8+ T cell differentiation in mice with chronic viral infection, we identified the alarmin interleukin-33 (IL-33) as pivotal for the expansion and stem-like functioning of CD8+SL as well as for virus control. IL-33 receptor (ST2)-deficient CD8+ T cells exhibited biased end differentiation and premature loss of Tcf-1. ST2-deficient CD8+SL responses were restored by blockade of type I interferon signaling, suggesting that IL-33 balances IFN-I effects to control CD8+SL formation in chronic infection. IL-33 signals broadly augmented chromatin accessibility in CD8+SL and determined these cells’ re-expansion potential. Our study identifies the IL-33-ST2 axis as an important CD8+SL-promoting pathway in the context of chronic viral infection. [Display omitted] •Interleukin-33 (IL-33) promotes the expansion of stem-like CD8 T cells (CD8+SL)•IL-33 signals augment chromatin accessibility of CD8+SL in chronic viral infection•IL-33 prevents the loss of Tcf-1 expression by balancing type I interferon effects•IL-33 signaling to CD8+SL preserves these cells’ stemness and re-expansion capacity Stem-like Tcf-1-expressing CD8 T cells (CD8+SL) are key to immune defense in chronic infection and cancer, but the cytokine signals that promote CD8+SL cell expansion and stemness remain undefined. Marx et al. reveal that interleukin-33 assumes this role by balancing type I interferon signals and augmenting chromatin accessibility of CD8+SL.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1074-7613 1097-4180
DOI:	10.1016/j.immuni.2023.01.029