Tracking γδ T cell development and TCRγδ proximal signalling

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Publicações

Distinct metabolic programs established in the thymus control effector functions of γδ T cell subsets in tumor microenvironments

Publication . Lopes, Noel; McIntyre, Claire; Martin, Stefania; Raverdeau, Mathilde; Sumaria, Nital; Kohlgruber, Ayano C.; Fiala, Gina; Agudelo, Leandro Z.; Dyck, Lydia; Kane, Harry; Douglas, Aaron; Cunningham, Stephen; Prendeville, Hannah; Loftus, Roisin; Carmody, Colleen; Pierre, Philippe; Kellis, Manolis; Brenner, Michael; Argüello, Rafael J.; Silva-Santos, Bruno; Pennington, Daniel J.; Lynch, Lydia

Metabolic programming controls immune cell lineages and functions, but little is known about γδ T cell metabolism. Here, we found that γδ T cell subsets making either interferon-γ (IFN-γ) or interleukin (IL)-17 have intrinsically distinct metabolic requirements. Whereas IFN-γ+ γδ T cells were almost exclusively dependent on glycolysis, IL-17+ γδ T cells strongly engaged oxidative metabolism, with increased mitochondrial mass and activity. These distinct metabolic signatures were surprisingly imprinted early during thymic development and were stably maintained in the periphery and within tumors. Moreover, pro-tumoral IL-17+ γδ T cells selectively showed high lipid uptake and intracellular lipid storage and were expanded in obesity and in tumors of obese mice. Conversely, glucose supplementation enhanced the antitumor functions of IFN-γ+ γδ T cells and reduced tumor growth upon adoptive transfer. These findings have important implications for the differentiation of effector γδ T cells and their manipulation in cancer immunotherapy.

2021Artigo científico

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From thymus to periphery : molecular basis of effector γδ‐T cell differentiation

Publication . Fiala, Gina; Gomes, Anita Q.; Silva-Santos, Bruno

The contributions of γδ T cells to immune (patho)physiology in many pre-clinical mouse models have been associated with their rapid and abundant provision of two critical cytokines, interferon-γ (IFN-γ) and interleukin-17A (IL-17). These are typically produced by distinct effector γδ T cell subsets that can be segregated on the basis of surface expression levels of receptors such as CD27, CD44 or CD45RB, among others. Unlike conventional T cells that egress the thymus as naïve lymphocytes awaiting further differentiation upon activation, a large fraction of murine γδ T cells commits to either IFN-γ or IL-17 expression during thymic development. However, extrathymic signals can both regulate pre-programmed γδ T cells; and induce peripheral differentiation of naïve γδ T cells into effectors. Here we review the key cellular events of "developmental pre-programming" in the mouse thymus; and the molecular basis for effector function maintenance vs plasticity in the periphery. We highlight some of our contributions towards elucidating the role of T cell receptor, co-receptors (like CD27 and CD28) and cytokine signals (such as IL-1β and IL-23) in these processes, and the various levels of gene regulation involved, from the chromatin landscape to microRNA-based post-transcriptional control of γδ T cell functional plasticity.

2020Artigo científico

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Entidade financiadora

European Commission

Programa de financiamento

H2020

Número da atribuição

752932