The serine/threonine protein phosphatase 2A controls autoimmunity

Sharabi, Amir; Kasper, Isaac R.; Tsokos, George C.

doi:10.1016/j.clim.2017.07.012

Cited by 30 publications

(31 citation statements)

References 41 publications

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“…PP2A has been previously reported to be involved in autoimmune diseases in both human patients and mouse models. This could arise from dysregulated T cell differentiation as previously described (37,39). Our findings here provide another possible mechanism elevated PP2A expression might facilitate for the survival of autoreactive T cells during selection, thus increase the likelihood of autoimmune disease arising.…”

Section: Discussionsupporting

confidence: 69%

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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Section: Discussionsupporting

confidence: 69%

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 serine/threonine protein phosphatase 2A (PP2A) is a ubiquitous serine-threonine phosphatase and composed of three distinct subunits; the scaffold A subunit (PP2A A ), the regulatory B subunit (PP2A B ), and the catalytic C subunit (PP2A C ) ( 36 ). PP2A controls the expression of CD3ζ and FcRγ at the transcription level through the dephosphorylation of Elf-1 ( 37 ).…”

Section: T Cell Receptor (Tcr)mentioning

confidence: 99%

Aberrant T Cell Signaling and Subsets in Systemic Lupus Erythematosus

2018

Self Cite

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Systemic lupus erythematosus (SLE) is a chronic multi-organ debilitating autoimmune disease, which mainly afflicts women in the reproductive years. A complex interaction of genetics, environmental factors and hormones result in the breakdown of immune tolerance to “self” leading to damage and destruction of multiple organs, such as the skin, joints, kidneys, heart and brain. Both innate and adaptive immune systems are critically involved in the misguided immune response against self-antigens. Dendritic cells, neutrophils, and innate lymphoid cells are important in initiating antigen presentation and propagating inflammation at lymphoid and peripheral tissue sites. Autoantibodies produced by B lymphocytes and immune complex deposition in vital organs contribute to tissue damage. T lymphocytes are increasingly being recognized as key contributors to disease pathogenesis. CD4 T follicular helper cells enable autoantibody production, inflammatory Th17 subsets promote inflammation, while defects in regulatory T cells lead to unchecked immune responses. A better understanding of the molecular defects including signaling events and gene regulation underlying the dysfunctional T cells in SLE is necessary to pave the path for better management, therapy, and perhaps prevention of this complex disease. In this review, we focus on the aberrations in T cell signaling in SLE and highlight therapeutic advances in this field.

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“…84 85 96 Moreover, SLE T cells display abnormal T cell signalling. 83 97 In addition, exhausted CD4+ T cells with dysbalanced IL-17/IL-2 production have been reported. 83 The full impact of a broadly anergic adaptive immune system in SLE has not been fully delineated.…”

Section: Co-stimulation Of Cd40 Effectively Improves B Cell Anergy Inmentioning

confidence: 99%

Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus

et al. 2020

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Systemic lupus erythematosus (SLE) is characterised by numerous abnormalities in B lineage cells, including increased CD27++ plasmablasts/plasma cells, atypical CD27-IgD- B cells with increased CD95, spleen tyrosine kinase (Syk)++, CXCR5- and CXCR5+ subsets and anergic CD11c+Tbet+ age-associated B cells. Most findings, together with preclinical lupus models, support the concept of B cell hyperactivity in SLE. However, it remains largely unknown whether these specific B cell subsets have pathogenic consequences and whether they provide relevant therapeutic targets. Recent findings indicate a global distortion of B cell functional capability, in which the entire repertoire of naïve and memory B cells in SLE exhibits an anergic or postactivated (APA) functional phenotype. The APA status of SLE B cells has some similarities to the functional derangement of lupus T cells. APA B cells are characterised by reduced global cytokine production, diminished B cell receptor (BCR) signalling with decreased Syk and Bruton’s tyrosine kinase phosphorylation related to repeated in vivo BCR stimulation as well as hyporesponsiveness to toll-like receptor 9 engagement, but intact CD40 signalling. This APA status was related to constitutive co-localisation of CD22 linked to phosphatase SHP-1 and increased overall protein phosphatase activities. Notably, CD40 co-stimulation could revert this APA status and restore BCR signalling, downregulate protein tyrosine phosphatase transcription and promote B cell proliferation and differentiation. The APA status and their potential rescue by bystander help conveyed through CD40 stimulation not only provides insights into possible mechanisms of escape of autoreactive clones from negative selection but also into novel ways to target B cells therapeutically.

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The serine/threonine protein phosphatase 2A controls autoimmunity

Cited by 30 publications

References 41 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

Aberrant T Cell Signaling and Subsets in Systemic Lupus Erythematosus

Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus

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