IL-21 conditions antigen-presenting human γδ T-cells to promote IL-10 expression in naïve and memory CD4+ T-cells

Tyler, Christopher J., Hoti, Inva, Griffiths, Daniel D. ORCID: https://orcid.org/0009-0001-5312-511X, Cuff, Simone M., Andrews, Robert, Keisker, Maximilian, Ahmed, Raya, Hansen, Hinrich P., Lindsay, James O., Stagg, Andrew J., Moser, Bernhard ORCID: https://orcid.org/0000-0002-4354-4572, McCarthy, Neil E. and Eberl, Matthias ORCID: https://orcid.org/0000-0002-9390-5348 2024. IL-21 conditions antigen-presenting human γδ T-cells to promote IL-10 expression in naïve and memory CD4+ T-cells. Discovery Immunology 10.1093/discim/kyae008

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Abstract

Direct interaction between T-cells exerts a major influence on tissue immunity and inflammation across multiple body sites including the human gut, which is highly enriched in ‘unconventional’ lymphocytes such as γδ T-cells. We previously reported that microbial activation of human Vγ9/Vδ2+ γδ T-cells in the presence of the mucosal damage-associated cytokine IL-15 confers the ability to promote epithelial barrier defence, specifically via induction of IL-22 expression in conventional CD4+ T-cells. In the current report, we assessed whether other cytokines enriched in the gut milieu also functionally influence microbe-responsive Vγ9/Vδ2 T-cells. When cultured in the presence of IL-21, Vγ9/Vδ2 T-cells acquired the ability to induce expression of the immunoregulatory cytokine IL-10 in both naïve and memory CD4+ T-cells, at levels surpassing those induced by monocytes or monocyte-derived DCs. These findings identify an unexpected influence of IL-21 on Vγ9/Vδ2 T-cell modulation of CD4+ T-cell responses. Further analyses suggested a possible role for CD30L and/or CD40L reverse signalling in mediating IL-10 induction by IL-21 conditioned Vγ9/Vδ2 T-cells. Our findings indicate that the local microenvironment exerts a profound influence on Vγ9/Vδ2 T-cell responses to microbial challenge, leading to induction of distinct functional profiles among CD4+ T-cells that may influence inflammatory events at mucosal surfaces. Targeting these novel pathways may offer therapeutic benefit in disorders such as inflammatory bowel disease.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Medicine
Publisher:	Oxford University Press
ISSN:	2754-2483
Date of First Compliant Deposit:	22 May 2024
Date of Acceptance:	29 April 2024
Last Modified:	22 May 2024 10:27
URI:	https://orca.cardiff.ac.uk/id/eprint/168888

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