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The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases
최제민,Alfred Bothwell 한국분자세포생물학회 2012 Molecules and cells Vol.33 No.3
Members of the nuclear receptor superfamily function as transcription factors involved in innate and adaptive im-munity as well as lipid metabolism. These highly conser-ved proteins participate in ligand-dependent or -indepen-dent regulatory mechanisms that affect gene expression. Peroxisome proliferator-activated receptors (PPARs), which include PPAR, PPAR/, and PPAR, are a group of nuclear receptor proteins that play diverse roles in cellular differentiation, development, and metabolism. Each PPAR subfamily is activated by different endogenous and synthetic ligands. Recent studies using specific ligand treatments and cell type-specific PPAR knockout mice have revealed important roles for these proteins in T-cell-related autoimmune diseases. Moreover, PPARs have been shown to regulate T-cell survival, activation, and CD4+ T helper cell differentiation into the Th1, Th2, Th17, and Treg lineages. Here, we review the studies that provide insight into the important regulatory roles of PPARs in T-cell activation, survival, proliferation, differentiation, and autoimmune disease.
Chae, W.-J.,Henegariu, O.,Lee, S.-K.,Bothwell, A. L. M. Proceedings of the National Academy of Sciences 2006 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.103 No.25
<P>Regulatory T cells that express the Foxp3 transcription factor play important roles in preventing autoimmune diseases. Although several studies have demonstrated that the lack of the forkhead DNA-binding domain of Foxp3 caused severe autoimmune disease in scurfy mutant mice, the other functional domains of Foxp3 are less well characterized. Here, we show that the deletion of glutamic acid (DeltaE250) in the leucine-zipper domain of Foxp3 causes a loss of hyporesponsiveness when compared with wild-type Foxp3 upon antigenic stimulation. CD4 T cells that ectopically express the glutamic acid mutant show significant losses of suppressor activity both in vitro and in vivo. We also demonstrate that regulation of both Th1- and Th2-type cytokine secretion in CD4 T cells that express wild-type Foxp3 is significantly altered by the deletion of glutamic acid. Defects are also observed in the expression of adhesion molecules, such as l-selectin (CD62L) and CD103, suggesting an important role of glutamic acid in the migratory behavior of regulatory T cells. Finally, this mutation reduces transcriptional repressor activity and impairs the homodimerization of Foxp3. Taken together, our results provide insight into the mechanism that controls autoimmune diseases via the deletion of this single glutamic acid residue in the leucine-zipper domain of Foxp3.</P>
Lim, Sangho,Kirkiles-Smith, Nancy C.,Pober, Jordan S.,Bothwell, Alfred L.M.,Choi, Je-Min Elsevier 2018 Biomaterials Vol.183 No.-
<P><B>Abstract</B></P> <P>Manipulation of human T cell functioning by delivery of macromolecules such as DNA, RNA, or protein is limited, unless the human T cells have been stimulated or electropermeabilized. To achieve successful adaptation and survival of a grafted organ, the alloreactive T cells that induce graft rejection must be regulated. Corticosteroids, calcineurin inhibitors, and mTOR inhibitors, which are systemic immunosuppressants, are currently used for transplantation, with significant side effects. In this study, we demonstrated that a cell-permeable peptide (CPP), dNP2, could efficiently deliver proteins into human CD4 and CD8 T cells. We confirmed regulatory functioning of the cytoplasmic domain of CTLA-4 conjugated with dNP2 (dNP2-ctCTLA-4) in human T cell activation, proliferation, and chemokine receptor expression. We utilized a human skin allograft system in SCID/beige mice to examine whether dNP2-ctCTLA-4 could inhibit allograft rejection by controlling T cell responses. The grafted skin tissue inflammation, allogeneic T cell infiltration, and blood cytokine level was markedly reduced by dNP2-ctCTLA-4, resulting in successful transplantation. In addition, it also inhibited T cell alloresponses against microvessels formed form Bcl-2-transduced human umbilical vein endothelial cells implanted into Balb/c Rag1<SUP>−/−</SUP>/IL-2Rγ<SUP>−/-</SUP> double knockout (DKO) mice, assessed as reduced T cell infiltration and granzyme B expression. These results collectively suggest that dNP2 peptide conjugation offers a valuable tool for delivering macromolecules like proteins into human T cells, and dNP2-ctCTLA-4 is a novel agent that shows potential in controlling human T cell responses to allow successful adaptation of grafted tissues.</P>
Sex-Based Selectivity of PPARγ Regulation in Th1, Th2, and Th17 Differentiation
Park, Hong-Jai,Park, Hyeon-Soo,Lee, Jae-Ung,Bothwell, Alfred L. M.,Choi, Je-Min MDPI 2016 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.17 No.8
<P>Peroxisome proliferator-activated receptor gamma (PPARγ) has recently been recognized to regulate adaptive immunity through Th17 differentiation, Treg functions, and T<SUB>FH</SUB> responses. However, its role in adaptive immunity and autoimmune disease is still not clear, possibly due to sexual differences. Here, we investigated in vitro treatment study with the PPARγ agonist pioglitazone to compare Th1, Th2, and Th17 differentiation in male and female mouse splenic T cells. Pioglitazone treatment significantly inhibited various effector T cell differentiations including Th1, Th2, and Th17 cells from female naïve T cells, but it selectively reduced IL-17 production in male Th17 differentiation. Interestingly, pioglitazone and estradiol (E2) co-treatment of T cells in males inhibited differentiation of Th1, Th2, and Th17 cells, suggesting a mechanism for the greater sensitivity of PPARγ to ligand treatment in the regulation of effector T cell differentiation in females. Collectively, these results demonstrate that PPARγ selectively inhibits Th17 differentiation only in male T cells and modulates Th1, Th2, and Th17 differentiation in female T cells based on different level of estrogen exposure. Accordingly, PPARγ could be an important immune regulator of sexual differences in adaptive immunity.</P>
Park, Tae-Yoon,Park, Sung-Dong,Cho, Jen-Young,Moon, Jae-Seung,Kim, Na-Yeon,Park, Kyungsoo,Seong, Rho Hyun,Lee, Sang-Won,Morio, Tomohiro,Bothwell, Alfred L. M.,Lee, Sang-Kyou National Academy of Sciences 2014 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.111 No.52
<P>The nuclear hormone receptor retinoic acid-related orphan receptor gamma t (ROR gamma t) is a transcription factor (TF) specific to T(H)17 cells that produce interleukin (IL)-17 and have been implicated in a wide range of autoimmunity. Here, we developed a novel therapeutic strategy to modulate the functions of ROR gamma t using cell-transducible form of transcription modulation domain of ROR gamma t (tROR gamma t-TMD), which can be delivered effectively into the nucleus of cells and into the central nerve system (CNS). tROR gamma t-TMD specifically inhibited T(H)17-related cytokines induced by ROR gamma t, thereby suppressing the differentiation of naive T cells into T(H)17, but not into T(H)1, T(H)2, or Treg cells. tROR gamma t-TMD injected into experimental autoimmune encephalomyelitis (EAE) animal model can be delivered effectively in the splenic CD4(+) T cells and spinal cord-infiltrating CD4(+) T cells, and suppress the functions of T(H)17 cells. The clinical severity and incidence of EAE were ameliorated by tROR gamma t-TMD in preventive and therapeutic manner, and significant reduction of both infiltrating CD4(+) IL-17(+) T cells and inflammatory cells into the CNS was observed. As a result, the number of spinal cord demyelination was also reduced after tROR gamma t-TMD treatment. With the same proof of concept, tTbet-TMD specifically blocking T(H)1 differentiation improved the clinical incidence of rheumatoid arthritis (RA). Therefore, tROR gamma t-TMD and tTbet-TMD can be novel therapeutic reagents with the natural specificity for the treatment of inflammatory diseases associated with T(H)17 or T(H)1. This strategy can be applied to treat various diseases where a specific transcription factor has a key role in pathogenesis.</P>
T Cell Receptor-MHC Class I Peptide Interactions : Affinity, Kinetics, and Specificity
Corr, Maripat,Slanetz, Alfred E.,Boyd, Lisa F.,Jelonek, Marie T.,Khilko, Sergei,Al-Ramadi, Basel K.,Kim, Young Sang,Maher, Stephen E.,Bothwell, Alfred L. M.,Margulies, David H. 충남대학교 생물공학연구소 1996 생물공학연구지 Vol.4 No.-
The critical discriminatory event in the activation of T lymphocytes bearing αβT cell receptors (TCRs) is their interaction with a molecular complex consisting of a peptide bound to a major histocompatibility complex (MHC)-encoded classⅠor class Ⅱ molecule on the surface of an antigen-presenting cell. The kinetics of binding were measured of a purified TCR to molecular complexes of a purified soluble analog of the murine MHC classⅠ molecule H-2L^d (sH-2L^d) and a synthetic octamer peptide p2CL in a direct, real-time assay based on surface plasmon resonance. The kinetic dissociation rate of the MHC-peptide complex from the TCR was rapid (2.6×10^-2) second^-1, corresponding to a half-time for dissociation of approximately 27 seconds), and the kinetic association rate was 2.1×10^ 5 M^-1 second^-1. The equilibrium constant for dissociation was approximately 10^-7M These values indicate that TCRs must interact with a multivalent array of MHC-peptide complexes to trigger T cell signaling.
Moon, Jae-Seung,Mun, Chin Hee,Kim, Jung-Ho,Cho, Jen-Young,Park, Sung-Dong,Park, Tae-Yoon,Shin, Jin-Su,Ho, Chun-Chang,Park, Yong-Beom,Ghosh, Sankar,Bothwell, Alfred L.M.,Lee, Sang-Won,Lee, Sang-Kyou Springer-Verlag 2018 Kidney international Vol.93 No.5
<P>Excessive expression of Tbet and IFN gamma is evidence of systemic lupus erythematosus (SLE) in lupus patients. In this study, the nucleus-transducible form of Transcription Modulation Domain (TMD) of Tbet (ntTbet-TMD), which is a fusion protein between Protein Transduction Domain Hph-1 (Hph-1-PTD) and the TMD of Tbet comprising DNA binding domain and isotype-specific domain, was generated to inhibit Tbet-mediated transcription in the interactomic manner. ntTbet-TMD was effectively delivered into the nucleus of the cells and specifically inhibited Tbet-mediated transcription without influencing the differentiation of other T cell subsets and signaling events for T cell activation. The severity of nephritis was significantly reduced by ntTbet-TMD as effectively as methylprednisolone in lupus-prone mice. The number of Th1, Th2 or Th17 cells and the secretion of their cytokines substantially decreased in the spleen and kidney of lupus-prone mice by ntTbet-TMD treatment. In contrast to methylprednisolone, the marked increase of Treg cells and the secretion of their immunosuppressive cytokine were detected in the spleen of (NZB/NZW) F1 mice treated with ntTbet-TMD. Thus, ntTbet-TMD can improve nephritis in lupus-prone mice by modulating the overall proinflammatory microenvironment and rebalancing T cell subsets, leading to new immune therapeutics for Th1-mediated autoimmune diseases.</P>