The CD4(+) regulatory T (Treg) cell lineage, defined by FOXP3 expression, comprises thymus-derived (t)Treg cells and peripherally induced (p)Treg cells. As a model for Treg cells, studies employ... Show moreThe CD4(+) regulatory T (Treg) cell lineage, defined by FOXP3 expression, comprises thymus-derived (t)Treg cells and peripherally induced (p)Treg cells. As a model for Treg cells, studies employ TGF-beta-induced (i)Treg cells generated from CD4(+) conventional T (Tconv) cells in vitro. Here, we describe how human iTreg cells relate to human blood-derived tTreg and Tconv cells according to proteomic analysis. Each of these cell populations had a unique protein expression pattern. iTreg cells had very limited overlap in protein expression with tTreg cells, regardless of cell activation status and instead shared signaling and metabolic proteins with Tconv cells. tTreg cells had a uniquely modest response to CD3/CD28-mediated stimulation. As a benchmark, we used a previously defined proteomic signature that discerns ex vivo naive and effector Treg cells from Tconv cells and includes conserved Treg cell properties. iTreg cells largely lacked this Treg cell core signature and highly expressed e.g. STAT4 and NFATC2, which may contribute to inflammatory responses. We also used a proteomic signature that distinguishes ex vivo effector Treg cells from Tconv cells and naive Treg cells. iTreg cells contained part of this effector Treg cell signature, suggesting acquisition of pTreg cell features. In conclusion, iTreg cells are distinct from tTreg cells and share limited features with ex vivo Treg cells at the proteomic level. Show less
Mensink, M.; Tran, T.N.M.; Zaal, E.A.; Schrama, E.; Berkers, C.R.; Borst, J.; Kivit, S. de 2022
CD4(+) conventional T cells (Tconvs) mediate adaptive immune responses, whereas regulatory T cells (Tregs) suppress those responses to safeguard the body from autoimmunity and inflammatory diseases... Show moreCD4(+) conventional T cells (Tconvs) mediate adaptive immune responses, whereas regulatory T cells (Tregs) suppress those responses to safeguard the body from autoimmunity and inflammatory diseases. The opposing activities of Tconvs and Tregs depend on the stage of the immune response and their environment, with an orchestrating role for cytokine- and costimulatory receptors. Nutrient availability also impacts T-cell functionality via metabolic and biosynthetic processes that are largely unexplored. Many data argue that costimulation by Tumor Necrosis Factor Receptor 2 (TNFR2) favors support of Treg over Tconv responses and therefore TNFR2 is a key clinical target. Here, we review the pertinent literature on this topic and highlight the newly identified role of TNFR2 as a metabolic regulator for thymus-derived (t)Tregs. We present novel transcriptomic and metabolomic data that show the differential impact of TNFR2 on Tconv and tTreg gene expression and reveal distinct metabolic impact on both cell types. Show less
Mensink, M.; Tran, T.N.M.; Zaal, E.A.; Schrama, E.; Berkers, C.R.; Borst, J.; Kivit, S. de 2022
CD4+ conventional T cells (Tconvs) mediate adaptive immune responses, whereas regulatory T cells (Tregs) suppress those responses to safeguard the body from autoimmunity and inflammatory diseases.... Show moreCD4+ conventional T cells (Tconvs) mediate adaptive immune responses, whereas regulatory T cells (Tregs) suppress those responses to safeguard the body from autoimmunity and inflammatory diseases. The opposing activities of Tconvs and Tregs depend on the stage of the immune response and their environment, with an orchestrating role for cytokine- and costimulatory receptors. Nutrient availability also impacts T-cell functionality via metabolic and biosynthetic processes that are largely unexplored. Many data argue that costimulation by Tumor Necrosis Factor Receptor 2 (TNFR2) favors support of Treg over Tconv responses and therefore TNFR2 is a key clinical target. Here, we review the pertinent literature on this topic and highlight the newly identified role of TNFR2 as a metabolic regulator for thymus-derived (t)Tregs. We present novel transcriptomic and metabolomic data that show the differential impact of TNFR2 on Tconv and tTreg gene expression and reveal distinct metabolic impact on both cell types. Show less
Mensink, M.; Tran, T.N.M.; Zaal, E.A.; Schrama, E.; Berkers, C.R.; Borst, J.; Kivit, S. de 2022
CD4(+) conventional T cells (Tconvs) mediate adaptive immune responses, whereas regulatory T cells (Tregs) suppress those responses to safeguard the body from autoimmunity and inflammatory diseases... Show moreCD4(+) conventional T cells (Tconvs) mediate adaptive immune responses, whereas regulatory T cells (Tregs) suppress those responses to safeguard the body from autoimmunity and inflammatory diseases. The opposing activities of Tconvs and Tregs depend on the stage of the immune response and their environment, with an orchestrating role for cytokine- and costimulatory receptors. Nutrient availability also impacts T-cell functionality via metabolic and biosynthetic processes that are largely unexplored. Many data argue that costimulation by Tumor Necrosis Factor Receptor 2 (TNFR2) favors support of Treg over Tconv responses and therefore TNFR2 is a key clinical target. Here, we review the pertinent literature on this topic and highlight the newly identified role of TNFR2 as a metabolic regulator for thymus-derived (t)Tregs. We present novel transcriptomic and metabolomic data that show the differential impact of TNFR2 on Tconv and tTreg gene expression and reveal distinct metabolic impact on both cell types. Show less
Kivit, S. de; Mensink, M.; Hoekstra, A.T.; Berlin, I.; Derks, R.J.E.; Both, D.; ... ; Borst, J. 2020
Following activation, conventional T (T-conv) cells undergo an mTOR-driven glycolytic switch. Regulatory T (T-reg) cells reportedly repress the mTOR pathway and avoid glycolysis. However, here we... Show moreFollowing activation, conventional T (T-conv) cells undergo an mTOR-driven glycolytic switch. Regulatory T (T-reg) cells reportedly repress the mTOR pathway and avoid glycolysis. However, here we demonstrate that human thymus-derived T-reg (tT(reg)) cells can become glycolytic in response to tumour necrosis factor receptor 2 (TNFR2) costimulation. This costimulus increases proliferation and induces a glycolytic switch in CD3-activated tT(reg) cells, but not in T-conv cells. Glycolysis in CD3-TNFR2-activated tT(reg) cells is driven by PI3-kinase-mTOR signalling and supports tT(reg) cell identity and suppressive function. In contrast to glycolytic T-conv cells, glycolytic tT(reg) cells do not show net lactate secretion and shuttle glucose-derived carbon into the tricarboxylic acid cycle. Ex vivo characterization of blood-derived TNFR2(hi)CD4(+)CD25(hi)CD127(lo) effector T cells, which were FOXP3(+)IKZF2(+), revealed an increase in glucose consumption and intracellular lactate levels, thus identifying them as glycolytic tT(reg) cells. Our study links TNFR2 costimulation in human tT(reg) cells to metabolic remodelling, providing an additional avenue for drug targeting. Show less
