RORγt limits the amount of the cytokine receptor γc through the prosurvival factor Bcl-x
            <sub>L</sub>
            in developing thymocytes

Ligons, Davinna L.; Waickman, Adam T.; Park, Jooyoung; Luckey, Megan A.; Park, Jung Hyun

doi:10.1126/scisignal.aam8939

Cited by 11 publications

(11 citation statements)

References 62 publications

(106 reference statements)

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“…Up-regulation of expression of survival-related proteins is one of the known mechanisms to promote thymocyte survival in this context. Well-studied examples include the Bcl-2 family prosurvival proteins Bcl-xL, whose stage-specific enrichment promotes the survival of DP thymocytes (6). In addition to regulations at the level of gene expression, further studies revealed that posttranslational modifications such as Ser/Thr phosphorylation of prosurvival proteins is also vital for thymocyte survival.…”

mentioning

confidence: 99%

Protein phosphatase 2A has an essential role in promoting thymocyte survival during selection

Zheng

Zhao

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The development of thymocytes to mature T cells in the thymus is tightly controlled by cellular selection, in which only a small fraction of thymocytes equipped with proper quality of TCRs progress to maturation. It is pivotal to protect the survival of the few T cells, which pass the selection. However, the signaling events, which safeguard the cell survival in thymus, are not totally understood. In this study, protein Ser/Thr phosphorylation in thymocytes undergoing positive selection is profiled by mass spectrometry. The results revealed large numbers of dephosphorylation changes upon T cell receptor (TCR) activation during positive selection. Subsequent substrate analysis pinpointed protein phosphatase 2A (PP2A) as the enzyme responsible for the dephosphorylation changes in developing thymocytes. PP2A catalytic subunit α (Ppp2ca) deletion in the T cell lineage in Ppp2ca flox/flox -Lck-Cre mice (PP2A cKO) displayed dysregulated dephosphorylation of apoptosis-related proteins in double-positive (DP) cells and caused substantially decreased numbers of DP CD4 + CD8 + cells. Increased levels of apoptosis in PP2A cKO DP cells were found to underlie aberrant thymocyte development. Finally, the defective thymocyte development in PP2A cKO mice could be rescued by either Bcl2 transgene expression or by p53 knockout. In summary, our work reveals an essential role of PP2A in promoting thymocyte development through the regulation of cell survival. thymocyte selection | PP2A | apoptosis T lymphocytes are the major form of adaptive immune cells that target pathogens (1, 2). T cell precursors originate in the bone marrow and then migrate to the thymus to initiate differentiation into mature T cells. In the thymus, CD4 -CD8doublenegative (DN) thymocytes (which can be subcategorized as stages DN1-DN4) acquire T cell receptor (TCR) expression through VDJ recombination and develop into CD4 + CD8 + double-positive (DP) thymocytes, which subsequently give rise to CD4 + or CD8 + single-positive (SP) T cells. Two pivotal selection processes occur, namely positive selection and negative selection, and both serve as gatekeepers in the progress of DP T cells to the SP stage. Notably, only a small percentage of DP thymocytes survive through the selection process to become mature T cells bearing TCRs with suitable reactivity. Secure survival of the T cells which do pass selection is then of pivotal importance during thymic development.It has been shown that TCRs on the DP cell surface can bind to self-peptide-major histocompatibility complex (MHC) complexes on thymic epithelial and dendritic cells, which provide signals for thymocyte survival (3-5). Up-regulation of expression of survival-related proteins is one of the known mechanisms to promote thymocyte survival in this context. Well-studied examples include the Bcl-2 family prosurvival proteins Bcl-xL, whose stage-specific enrichment promotes the survival of DP thymocytes (6). In addition to regulations at the level of gene expression, further studies revealed that posttranslational ...

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mentioning

confidence: 99%

Protein phosphatase 2A has an essential role in promoting thymocyte survival during selection

Zheng

Zhao

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Although these results indirectly support a RORγt requirement for CD138 expression, we consider it unlikely that RORγt expression is sufficient to induce CD138 expression on all T lineage cells. As such, we found that immature double-positive thymocytes, which comprise the main cell population in the thymus, expressed large amounts of RORγt but did not induce CD138 ( Figure 1A ) ( 23 ). These data indicated that CD138 expression is clearly associated with RORγt expression but that cellular factors other than RORγt also play roles in the induction of CD138 expression in T cells.…”

Section: Resultsmentioning

confidence: 84%

“…To this end, we examined thymic i NKT cells of RORγt-transgenic (RORγt Tg ) and WT littermate BALB/c mice for surface CD138 expression. RORγt Tg mice have been previously described ( 23 ), and they express the murine RORγt cDNA under the control of the proximal Lck promoter. Accordingly, all thymocytes, including thymic i NKT cells, are forced to express RORγt ( Supplemental Figure 6A ).…”

Section: Resultsmentioning

confidence: 99%

CD138 expression is a molecular signature but not a developmental requirement for RORγt+ NKT17 cells

Luo¹,

Kwon²,

Crossman³

et al. 2021

JCI Insight

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Invariant NKT ( i NKT) cells are potent immunomodulatory cells that acquire effector function during their development in the thymus. IL-17–producing i NKT cells are commonly referred to as NKT17 cells, and they are unique among i NKT cells to express the heparan sulfate proteoglycan CD138 and the transcription factor RORγt. Whether and how CD138 and RORγt contribute to NKT17 cell differentiation, and whether there is an interplay between RORγt and CD138 expression to control i NKT lineage fate, remain mostly unknown. Here, we showed that CD138 expression was only associated with and not required for the differentiation and IL-17 production of NKT17 cells. Consequently, CD138-deficient mice still generated robust numbers of IL-17–producing RORγt + NKT17 cells. Moreover, forced expression of RORγt significantly promoted the generation of thymic NKT17 cells, but did not induce CD138 expression on non-NKT17 cells. These results indicated that NKT17 cell generation and IL-17 production were driven by RORγt, employing mechanisms that were independent of CD138. Therefore, our study effectively dissociated CD138 expression from the RORγt-driven molecular pathway of NKT17 cell differentiation.

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“…1C ). Furthermore, the forced expression of RORγt ( Ligons et al, 2018 ), the master transcription factor of NKT17 cell development and function ( Tsagaratou, 2019 ), dramatically increased both the frequency and number of DR3-expressing i NKT cells ( Figure 1D ). These results suggested that DR3 expression is controlled downstream of RORγt so that all DR3 + thymic i NKT cells of RORγt Tg mice also expressed CD138 ( Figure 1D; Figure 1–figure supplement 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…BALB/cAnNCrl and C57BL/6 mice were purchased from the Charles River Laboratories. CD138-deficient ( Sdc1 −/− ) mice and RORγt Tg mice were previously described ( Alexander et al, 2000; Ligons et al, 2018; Luo et al, 2021 ), and these animals were backcrossed in-house onto BALB/cAnNCrl background before analyses. Foxp3-DTR/EGFP mice were obtained from the Jackson Laboratory and maintained on BALB/cAnNCrl background ( Lahl et al, 2007 ).…”

Section: Methodsmentioning

confidence: 99%

The cytokine receptor DR3 identifies and activates thymic NKT17 cells

Luo

Liman

Crossman

et al. 2021

Preprint

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Invariant natural killer T (iNKT) cells are thymus-generated T cells with innate-like characteristics and effector function. Several functionally distinct iNKT subsets have been identified, but NKT17 is the only iNKT subset that produces the proinflammatory cytokine IL-17. NKT17 cells are generated in the thymus and then exported into the periphery to populate lymphoid organs and barrier tissues, such as the lung, to provide critical support in host defense. However, the molecular mechanisms that drive the thymic development and subset-specific activation of NKT17 cells remain mostly unknown. Here, we identify the cytokine receptor DR3, a member of the TNF receptor superfamily, being selectively expressed on NKT17 cells but absent on all other thymic iNKT subsets. We further demonstrate that DR3 ligation leads to the in vivo activation of thymic NKT17 cells and provides in vitro costimulatory effects upon α-GalCer-stimulation. Thus, our study reports the identification of a specific surface marker for thymic NKT17 cells that selectively triggers their activation both in vivo and in vitro. These findings provide new insights for deciphering the role and function of IL-17-producing NKT17 cells and for understanding the development and activation mechanisms of iNKT cells in general.

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RORγt limits the amount of the cytokine receptor γc through the prosurvival factor Bcl-x _L in developing thymocytes

Cited by 11 publications

References 62 publications

Protein phosphatase 2A has an essential role in promoting thymocyte survival during selection

Protein phosphatase 2A has an essential role in promoting thymocyte survival during selection

CD138 expression is a molecular signature but not a developmental requirement for RORγt+ NKT17 cells

The cytokine receptor DR3 identifies and activates thymic NKT17 cells

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RORγt limits the amount of the cytokine receptor γc through the prosurvival factor Bcl-x L in developing thymocytes

Cited by 11 publications

References 62 publications

Protein phosphatase 2A has an essential role in promoting thymocyte survival during selection

Protein phosphatase 2A has an essential role in promoting thymocyte survival during selection

CD138 expression is a molecular signature but not a developmental requirement for RORγt+ NKT17 cells

The cytokine receptor DR3 identifies and activates thymic NKT17 cells

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Resources

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RORγt limits the amount of the cytokine receptor γc through the prosurvival factor Bcl-x _L in developing thymocytes