Publications (17)88.97 Total impact
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Article: Novel IL27p28/IL12p40 Cytokine Suppressed Experimental Autoimmune Uveitis by Inhibiting Autoreactive Th1/Th17 Cells and Promoting Expansion of Regulatory T Cells.
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ABSTRACT: IL-12 family cytokines are important in host immunity. Whereas some members (IL-12, IL-23) play crucial roles in pathogenesis of organ-specific autoimmune diseases by inducing the differentiation of Th1 and Th17 lymphocytes, others (IL-27 and IL-35) suppress inflammatory responses and limit tissue injury induced by these T cell subsets. In this study, we have genetically engineered a novel IL27p28/IL12p40 heterodimeric cytokine (p28/p40) that antagonizes signaling downstream of the gp130 receptor. We investigated whether p28/p40 can be used to ameliorate uveitis, a CNS inflammatory disease. Experimental autoimmune uveitis (EAU) is the mouse model of human uveitis and is mediated by Th1 and Th17 cells. We show here that p28/p40 suppressed EAU by inhibiting the differentiation and inflammatory responses of Th1 and Th17 cells while promoting expansion of IL-10(+)- and Foxp3(+)-expressing regulatory T cells. Lymph node cells from mice treated with p28/p40 blocked adoptive transfer of EAU to naïve syngeneic mice by immunopathogenic T cells and suppressive effects of p28/p40 derived in part from antagonizing STAT1 and STAT3 pathways induced by IL-27 and IL-6. Interestingly, IL27p28 also suppressed EAU, but to a lesser extent than p28/p40. The inhibition of uveitogenic lymphocyte proliferation and suppression of EAU by p28/p40 and IL27p28 establish efficacy of single chain and heterodimeric IL-12 family cytokines in treatment of a CNS autoimmune disease. Creation of the biologically active p28/p40 heterodimeric cytokine represents an important proof-of-concept experiment, suggesting that cytokines comprising unique IL-12 α- and β-subunit pairing may exist in nature and may constitute a new class of therapeutic cytokines.Journal of Biological Chemistry 08/2012; 287(43):36012-21. · 4.77 Impact Factor -
Article: Therapeutic targeting of STAT3 (signal transducers and activators of transcription 3) pathway inhibits experimental autoimmune uveitis.
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ABSTRACT: Mice with targeted deletion of STAT3 in CD4(+) T-cells do not develop experimental autoimmune uveitis (EAU) or experimental autoimmune encephalomyelitis (EAE), in part, because they cannot generate pathogenic Th17 cells. In this study, we have used ORLL-NIH001, a small synthetic compound that inhibits transcriptional activity of STAT3, to ameliorate EAU, an animal model of human posterior uveitis. We show that by attenuating inflammatory properties of uveitogenic lymphocytes, ORLL-NIH001 inhibited the recruitment of inflammatory cells into the retina during EAU and prevented the massive destruction of the neuroretina caused by pro-inflammatory cytokines produced by the autoreactive lymphocytes. Decrease in disease severity observed in ORLL-NIH001-treated mice, correlated with the down-regulation of α4β1 and α4β7 integrin activation and marked reduction of CCR6 and CXCR3 expression, providing a mechanism by which ORLL-NIH001 mitigated EAU. Furthermore, we show that ORLL-NIH001 inhibited the expansion of human Th17 cells, underscoring its potential as a drug for the treatment of human uveitis. Two synthetic molecules that target the Th17 lineage transcription factors, RORγt and RORα, have recently been suggested as potential drugs for inhibiting Th17 development and treating CNS inflammatory diseases. However, inhibiting STAT3 pathways completely blocks Th17 development, as well as, prevents trafficking of inflammatory cells into CNS tissues, making STAT3 a more attractive therapeutic target. Thus, use of ORLL-NIH001 to target the STAT3 transcription factor, thereby antagonizing Th17 expansion and expression of proteins that mediate T cell chemotaxis, provides an attractive new therapeutic approach for treatment of posterior uveitis and other CNS autoimmune diseases mediated by Th17 cells.PLoS ONE 01/2012; 7(1):e29742. · 4.09 Impact Factor -
Article: Persistence of IL-2 expressing Th17 cells in healthy humans and experimental autoimmune uveitis.
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ABSTRACT: Compared with other T-helper subsets, Th17 cell numbers are very low in human blood but become elevated in chronic inflammatory diseases. In this study, we investigated mechanisms that may explain the frequent involvement of Th17 cells in autoimmune diseases such as uveitis. We compared Th17 and Th1 subsets and found that Th17 cells expressed lower IL-2 levels during Ag-priming and this correlated with their decreased susceptibility to activation-induced cell death (AICD). However, complete depletion of IL-2 with IL-2 neutralizing antibodies rendered Th17 cells as susceptible to apoptosis as Th1 cells, suggesting that the low levels of IL-2 produced by Th17 cells conferred survival advantages to this subset. We describe here a Th17 subtype that constitutively produces very low levels of IL-2 (Th17-DP). The Th17-DP population increased dramatically in the blood and retina of mice during experimental autoimmune uveitis, indicating their potential involvement in the etiology of uveitis. We further show that the majority of the memory Th17 cells in human blood are Th17-DP and are targets of daclizumab, an IL-2R antibody used in treating recalcitrant uveitis. Thus, Th17 cells may persist in tissues and contribute to chronic inflammation by limiting IL-2 production to levels that cannot provoke IL-2-induced AICD yet are sufficient to promote Th17 homeostatic expansion.European Journal of Immunology 09/2011; 41(12):3495-505. · 5.10 Impact Factor -
Article: STAT3 Protein Promotes T-cell Survival and Inhibits Interleukin-2 Production through Up-regulation of Class O Forkhead Transcription Factors
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ABSTRACT: Much is known about the role of STAT3 in regulating differentiation of interleukin-17-producing Th17 cells, but its function in other lymphocyte subsets is not well understood. In this report, we reveal wide-ranging functions of STAT3 in T-cells and provide evidence that STAT3 is convergence point for mechanisms that regulate lymphocyte quiescence and those controlling T-cell activation and survival. We show here that STAT3 inhibits T-lymphocyte proliferation by up-regulating the expression of Class-O Forkhead transcription factors, which play essential roles in maintaining T-cells in quiescent state. We further show that STAT3 binds directly to FoxO1 or FoxO3a promoter and that STAT3-deficiency resulted in down-regulation of the expression of FoxO1, FoxO3a and FoxO-target genes (IκB and p27Kip1). Compared with wild-type T-cells, STAT3-deficient T-cells produced more IL-2, due in part, to marked decrease in IκB-mediated sequestration of NF-κB in the cytoplasm and resultant enhancement of NF-κB activation. However, the high level of IL-2 production by STAT3-deficient T-cells was partially restored to normal levels by overexpressing FoxO1. It is notable that their exaggerated increase in IL-2 production rendered STAT3-deficient lymphocytes more susceptible to activation-induced cell death, suggesting that STAT3 might protect T-cells from apoptosis by limiting their production of IL-2 through up-regulation of FoxO1/FoxO3a expression. Moreover, we found that STAT3 enhanced survival of activated T-cells by up-regulating OX-40 and Bcl-2 while down-regulating FasL and Bad expression, suggesting that similar to role of FoxOs in regulating the lifespan of worms, STAT3 and FoxO pathways converge to regulate lifespan of T-lymphocytes.Journal of Biological Chemistry 09/2011; 286(35):30888-30897. · 4.77 Impact Factor -
Article: STAT3 protein promotes T-cell survival and inhibits interleukin-2 production through up-regulation of Class O Forkhead transcription factors.
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ABSTRACT: Much is known about the role of STAT3 in regulating differentiation of interleukin-17-producing Th17 cells, but its function in other lymphocyte subsets is not well understood. In this report, we reveal wide-ranging functions of STAT3 in T-cells and provide evidence that STAT3 is convergence point for mechanisms that regulate lymphocyte quiescence and those controlling T-cell activation and survival. We show here that STAT3 inhibits T-lymphocyte proliferation by up-regulating the expression of Class-O Forkhead transcription factors, which play essential roles in maintaining T-cells in quiescent state. We further show that STAT3 binds directly to FoxO1 or FoxO3a promoter and that STAT3-deficiency resulted in down-regulation of the expression of FoxO1, FoxO3a and FoxO-target genes (IκB and p27Kip1). Compared with wild-type T-cells, STAT3-deficient T-cells produced more IL-2, due in part, to marked decrease in IκB-mediated sequestration of NF-κB in the cytoplasm and resultant enhancement of NF-κB activation. However, the high level of IL-2 production by STAT3-deficient T-cells was partially restored to normal levels by overexpressing FoxO1. It is notable that their exaggerated increase in IL-2 production rendered STAT3-deficient lymphocytes more susceptible to activation-induced cell death, suggesting that STAT3 might protect T-cells from apoptosis by limiting their production of IL-2 through up-regulation of FoxO1/FoxO3a expression. Moreover, we found that STAT3 enhanced survival of activated T-cells by up-regulating OX-40 and Bcl-2 while down-regulating FasL and Bad expression, suggesting that similar to role of FoxOs in regulating the lifespan of worms, STAT3 and FoxO pathways converge to regulate lifespan of T-lymphocytes.Journal of Biological Chemistry 07/2011; 286(35):30888-97. · 4.77 Impact Factor -
Article: STAT3 promotes T cell survival and inhibits IL-2 production through up-regulation of Class O Forkhead transcription factors
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ABSTRACT: Much is known about the role of STAT3 in regulating differentiation of Interleukin-17-producing Th17 cells but its function in other lymphocyte subsets is not well understood. In this report, we reveal wide-ranging functions of STAT3 in T-cells and provide evidence that STAT3 is convergence point for mechanisms that regulate lymphocyte quiescence and those controlling T-cell activation and survival. We show here that STAT3 inhibits T-lymphocyte proliferation by up-regulating the expression of Class-O Forkhead transcription factors, which play essential roles in maintaining T-cells in quiescent state. We further show that STAT3 binds directly to FoxO1 or FoxO3a promoter and that STAT3-deficiency resulted in downregulation of the expression of FoxO1, FoxO3a and FoxO-target genes (IκB and p27Kip1). Compared to wild-type T-cells, STAT3-deficient T-cells produced more IL-2, due in part, to marked decrease in IκB-mediated sequestration of NF-κB in the cytoplasm and resultant enhancement of NF-κB activation. However, the high level of IL-2 production by STAT3-deficient T-cells was partially restored to normal levels by over-expressing FoxO1. It is notable that their exaggerated increase in IL-2 production rendered STAT3-deficient lymphocytes more susceptible to activation-induced cell death, suggesting that STAT3 might protect T-cells from apoptosis by limiting their production of IL-2 through upregulation of FoxO1/FoxO3a expression. Moreover, we found that STAT3 enhanced survival of activated T-cells by up-regulating OX-40 and Bcl-2 while down-regulating FasL and Bad expression, suggesting that similar to role of FoxOs in regulating the lifespan of worms, STAT3 and FoxO pathways may converge to regulate lifespan of T-lymphocytes.Journal of Biological Chemistry 07/2011; · 4.77 Impact Factor -
Article: SOCS1 regulates CCR7 expression and migration of CD4+ T cells into peripheral tissues.
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ABSTRACT: Suppressors of cytokine signaling (SOCS) proteins control many aspects of lymphocyte function through regulation of STAT pathways. SOCS1-deficient mice develop severe skin and eye diseases that result from massive infiltration of inflammatory cells into these tissues. In this study, we have used SOCS1-, STAT1-, or STAT6-deficient mice, as well as, T cells with stable overexpression or deletion of SOCS1, to examine whether SOCS1 is involved in regulating lymphocyte trafficking to peripheral tissues. We show that SOCS1-deficient mice have increased numbers of T cells with characteristics of effector memory cells and expression of CCR7, a protein that promotes retention of T cells in lymphoid tissues, is markedly reduced in these cells. The decrease in CCR7 expression correlates with hyperactivation of STAT6, suggesting that aberrant recruitment of T cells into SOCS1-deficient mouse skin or eye results from abrogation of negative feedback regulation of STAT6 activation and CCR7 expression. Consistent with in vivo regulation of CCR7 expression and lymphocyte migration by SOCS1, forced overexpression of SOCS1 in T cells up-regulates CCR7 expression and enhances chemotaxis toward CCL19 or CCL21. CCR6 and CXCR3 are also up-regulated on SOCS1-deficient T cells and in situ analysis of the cornea or retina further reveal that these cells may mediate the chronic skin and eye inflammation through recruitment of Th1 and Th17 cells into these tissues. Collectively, these results suggest that SOCS1 regulates steady-state levels of chemokine receptors through its inhibitory effects on STAT pathways and this may underscore its role in regulating recruitment and retention of effector cells into nonlymphoid tissues.The Journal of Immunology 08/2008; 181(2):1190-8. · 5.79 Impact Factor -
Article: Hydrodynamic vaccination with DNA encoding an immunologically privileged retinal antigen protects from autoimmunity through induction of regulatory T cells.
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ABSTRACT: The eye is an immunologically privileged organ whose Ags serve as targets for experimental autoimmune uveitis (EAU), a model for human uveitis. We used a hydrodynamic i.v. injection of naked DNA to express the uveitogenic retinal Ag interphotoreceptor retinoid-binding protein (IRBP) in the periphery, thus revoking its immune-privileged status. IRBP was expressed in the liver within hours of administration of as little as 10 microg of IRBP-DNA. Vaccinated mice were highly protected from EAU induced by immunization with IRBP for at least 10 wk after vaccination. Protection was partial in a reversal protocol. Mechanistic studies revealed specific hyporesponsiveness to IRBP without immune deviation, no evidence for apoptosis either by the Fas- or Bcl-2-regulated (mitochondrial) pathway and apparent lack of dependence on CD8(+) cells, IL-10, or TGF-beta. In contrast, depletion of CD25(+) cells after vaccination and before challenge markedly abrogated protection. IRBP-specific CD4(+)CD25(high) T cells could be cultured from vaccinated mice and transferred protection to unvaccinated, EAU-challenged recipients. In vitro characterization of these cells revealed that they are Ag specific, anergic, express FoxP3, CTLA-4, and glucocorticoid-induced TNFR, and suppress by contact. Thus, expression of IRBP in the periphery by DNA vaccination results in tolerance that acts at least in part through induction of IRBP-specific, FoxP3(+)CD4(+)CD25(+) regulatory T cells. DNA vaccination may offer a new approach to Ag-specific therapy of uveitis.The Journal of Immunology 11/2007; 179(8):5146-58. · 5.79 Impact Factor -
Article: TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1
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ABSTRACT: T-helper type 17 cells (TH17) are implicated in rodent models of immune-mediated diseases. Here we report their involvement in human uveitis and scleritis, and validate our findings in experimental autoimmune uveoretinitis (EAU), a model of uveitis. TH17 cells were present in human peripheral blood mononuclear cells (PBMC), and were expanded by interleukin (IL)-2 and inhibited by interferon (IFN)-. Their numbers increased during active uveitis and scleritis and decreased following treatment. IL-17 was elevated in EAU and upregulated tumor necrosis factor (TNF)- in retinal cells, suggesting a mechanism by which TH17 may contribute to ocular pathology. Furthermore, IL-27 was constitutively expressed in retinal ganglion and photoreceptor cells, was upregulated by IFN- and inhibited proliferation of TH17. These findings suggest that TH1 cells may mitigate uveitis by antagonizing the TH17 phenotype through the IFN-–mediated induction of IL-27 in target tissue. The finding that IL-2 promotes TH17 expansion provides explanations for the efficacy of IL-2R antibody therapy in uveitis, and suggests that antagonism of TH17 by IFN- and/or IL-27 could be used for the treatment of chronic inflammation.Nature Medicine 05/2007; 13(6):711-718. · 22.46 Impact Factor -
Article: Cytokine-induced retinal degeneration: role of suppressors of cytokine signaling (SOCS) proteins in protection of the neuroretina.
Advances in experimental medicine and biology 02/2006; 572:275-81. · 1.09 Impact Factor -
Article: Thymic expression of peripheral tissue antigens in humans: a remarkable variability among individuals.
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ABSTRACT: The majority of maturing T lymphocytes that recognize self-antigens is eliminated in the thymus upon exposure to their target antigens. This physiological process of negative selection requires that tissue-specific antigens be expressed by thymic cells, a phenomenon that has been well studied in experimental animals. Here, we have examined the expression in human thymi of four retinal antigens, that are capable of inducing autoimmune ocular disease retinal S-antigen (S-Ag), recoverin, RPE65 and inter-photoreceptor retinoid-binding protein (IRBP)], as well as four melanocyte-specific antigens, two of which are used as targets for melanoma immunotherapy [gp100, melanoma antigen recognized by T cells 1, tyrosinase-related protein (TRP)-1 and TRP-2]. Using reverse transcription (RT)-PCR, we found that all thymic samples from the 18 donors expressed mRNA transcripts of most or all the eight tested tissue antigens. Yet, the expression of the transcripts varied remarkably among the individual thymic samples. In addition, S-Ag, RPE65 and IRBP were detected by immunostaining in rare cells in sections of human thymi by antibodies against these proteins. Quantitative real-time RT-PCR analysis revealed that the retinal antigen transcripts in the human thymus are present at trace levels, that are lower by approximately five orders of magnitude than those in the retina. Our observations thus support the notions that thymic expression is a common feature for all tissue-specific antigens and that the levels of expression play a role in determining the susceptibility to autoimmunity against these molecules.International Immunology 09/2005; 17(8):1131-40. · 3.41 Impact Factor -
Article: Cell proliferation and STAT6 pathways are negatively regulated in T cells by STAT1 and suppressors of cytokine signaling.
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ABSTRACT: Suppressor of cytokine signaling (SOCS) proteins have emerged as important regulators of cytokine signals in lymphocytes. In this study, we have investigated regulation of SOCS expression and their role in Th cell growth and differentiation. We show that SOCS genes are constitutively expressed in naive Th cells, albeit at low levels, and are differentially induced by Ag and Th-polarizing cytokines. Whereas cytokines up-regulate expression of SOCS1, SOCS2, SOCS3, and cytokine-induced Src homology 2 protein, Ags induce down-regulation of SOCS3 within 48 h of Th cell activation and concomitantly up-regulate SOCS1, SOCS2, and cytokine-induced Src homology 2 protein expression. We further show that STAT1 signals play major roles in inducing SOCS expression in Th cells and that induction of SOCS expression by IL-4, IL-12, or IFN-gamma is compromised in STAT1-deficient primary Th cells. Surprisingly, IL-4 is a potent inducer of STAT1 activation in Th2 but not Th1 cells, and SOCS1 or SOCS3 expression is dramatically reduced in STAT1(-/-) Th2 cells. To our knowledge, this is the first report of IL-4-induced STAT1 activation in Th cells, and suggests that its induction of SOCS, may in part, regulate IL-4 functions in Th2 cells. In fact, overexpression of SOCS1 in Th2 cells represses STAT6 activation and profoundly inhibits IL-4-induced proliferation, while depletion of SOCS1 by an anti-sense SOCS1 cDNA construct enhances cell proliferation and induces constitutive activation of STAT6 in Th2 cells. These results are consistent with a model where IL-4 has dual effects on differentiating T cells: it simulates proliferation/differentiation through STAT6 and autoregulates its effects on Th2 growth and effector functions via STAT1-dependent up-regulation of SOCS proteins.The Journal of Immunology 08/2004; 173(2):737-46. · 5.79 Impact Factor -
Article: Dendritic cell maturation requires STAT1 and is under feedback regulation by suppressors of cytokine signaling.
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ABSTRACT: In this study we show that activation of STAT pathways is developmentally regulated and plays a role in dendritic cell (DC) differentiation and maturation. The STAT6 signaling pathway is constitutively activated in immature DC (iDC) and declines as iDCs differentiate into mature DCs (mDCs). However, down-regulation of this pathway during DC differentiation is accompanied by dramatic induction of suppressors of cytokine signaling 1 (SOCS1), SOCS2, SOCS3, and cytokine-induced Src homology 2-containing protein expression, suggesting that inhibition of STAT6 signaling may be required for DC maturation. In contrast, STAT1 signaling is most robust in mDCs and is not inhibited by the up-regulated SOCS proteins, indicating that STAT1 and STAT6 pathways are distinctly regulated in maturing DC. Furthermore, optimal activation of STAT1 during DC maturation requires both IL-4 and GM-CSF, suggesting that synergistic effects of both cytokines may in part provide the requisite STAT1 signaling intensity for DC maturation. Analyses of STAT1(-/-) DCs reveal a role for STAT1 in repressing CD86 expression in precursor DCs and up-regulating CD40, CD11c, and SOCS1 expression in mDCs. We further show that SOCS proteins are differentially induced by IL-4 and GM-CSF in DCs. SOCS1 is primarily induced by IL-4 through a STAT1-dependent mechanism, whereas SOCS3 is induced mainly by GM-CSF. Taken together, these results suggest that cytokine-induced maturation of DCs is under feedback regulation by SOCS proteins and that the switch from constitutive activation of the STAT6 pathway in iDCs to predominant use of STAT1 signals in mDC is mediated in part by STAT1-induced SOCS expression.The Journal of Immunology 03/2004; 172(4):2307-15. · 5.79 Impact Factor -
Article: Suppressor of cytokine signaling 3 regulates proliferation and activation of T-helper cells.
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ABSTRACT: Suppressors of cytokine signaling (SOCS) have been implicated in regulation of T-cell activation and cytokine-mediated differentiation of T-helper cells. In this study we have characterized the pattern of SOCS expression in naïve and activated primary T-helper cells, examined whether expression of SOCS genes is regulated by cytokine or T-cell receptor signaling, and analyzed the function of SOCS in differentiated T-cells. We show that SOCS1, SOCS2, SOCS3, CIS (cytokine-induced SH2 protein) genes are constitutively expressed in naïve T-helper cells, with SOCS3 being the most abundant. Antigen stimulation of naïve T-helper cells down-regulates SOCS3 expression and concomitantly up-regulates SOCS1, SOCS2, and CIS gene transcription, suggesting that SOCS genes are regulated differentially by T-cell activation. Down-regulation of SOCS3 expression is subsequently followed by gradual increase in SOCS3 level and corresponding decline in interleukin 2 (IL-2) secretion. In fact, SOCS3 mRNA levels are inversely correlated with the amount of IL-2 secretion and proliferative responses of differentiating T-helper cells, suggesting mutually antagonistic effects of SOCS3 and IL-2 and feedback regulation of T-cell activation by SOCS3. Furthermore, the degree of SOCS3 inhibition is antigen concentration-dependent and is mediated in part by growth factor independence-1, a T-cell transcription factor that regulates S-phase entry in T-cells. Forced overexpression of SOCS3 inhibits proliferation of T-helper cells, whereas depletion of endogenous SOCS3 by antisense SOCS3 cDNA enhances T-cell receptor- and cytokine-induced proliferation. Taken together, these results suggest a role for SOCS3 in maintaining T-helper cells in a quiescent state. Transient inhibition of SOCS3 by antigen stimulation may therefore be essential in allowing activation of resting T-cells.Journal of Biological Chemistry 09/2003; 278(32):29752-9. · 4.77 Impact Factor -
Article: Suppressors of cytokine signaling proteins are differentially expressed in Th1 and Th2 cells: implications for Th cell lineage commitment and maintenance.
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ABSTRACT: Positive regulatory factors induced by IL-12/STAT4 and IL-4/STAT6 signaling during T cell development contribute to polarized patterns of cytokine expression manifested by differentiated Th cells. These two critical and antagonistic signaling pathways are under negative feedback regulation by a multimember family of intracellular proteins called suppressor of cytokine signaling (SOCS). However, it is not known whether these negative regulatory factors also modulate Th1/Th2 lineage commitment and maintenance. We show here that CD4(+) naive T cells constitutively express low levels of SOCS1, SOCS2, and SOCS3 mRNAs. These mRNAs and their proteins increase significantly in nonpolarized Th cells after activation by TCR signaling. We further show that differentiation into Th1 or Th2 phenotype is accompanied by preferential expression of distinct SOCS mRNA transcripts and proteins. SOCS1 expression is 5-fold higher in Th1 than in Th2 cells, whereas Th2 cells contain 23-fold higher levels of SOCS3. We also demonstrate that IL-12-induced STAT4 activation is inhibited in Th2 cells that express high levels of SOCS3 whereas IL-4/STAT6 signaling is constitutively activated in Th2 cells, but not Th1 cells, with high SOCS1 expression. These results suggest that mutually exclusive use of STAT4 and STAT6 signaling pathways by differentiated Th cells may derive in part, from SOCS3- or SOCS1-mediated repression of IL-12/STAT4- or IL-4/STAT6 signaling in Th2 and Th1 cells, respectively. Given the strong correlation between distinct patterns of SOCS expression and differentiation into the Th1 or Th2 phenotype, SOCS1 and SOCS3 proteins are therefore Th lineage markers that can serve as therapeutic targets for immune modulation therapy.The Journal of Immunology 05/2002; 168(7):3181-7. · 5.79 Impact Factor -
Article: Predominant usage of Vβ8.3 T cell receptor in a T cell line that induces experimental autoimmune uveoretinitis (EAU)
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ABSTRACT: Experimental autoimmune uveoretinitis (EAU) is a T cell-mediated autoimmune disease induced in animals by immunization with retinal proteins (or synthetic fragments derived from them) in adjuvant, and it is considered a model of human autoimmune diseases of the eye. To study the T cell clonotypes that may be involved in EAU, we analyzed the T cell repertoire of three related T cell lines: the pathogenic line LR16, specific to the major uveitogenic epitope of IRBP; its pathogenic subline J; and its nonpathogenic subline A. We examined the expression of the genes coding for the variable regions of the 20 known Lewis rat T cell antigen receptor (TCR) Vβ families. The nonpathogenic subline was found to contain mostly T cells expressing Vβ5, Vβ8.2, and Vβ19 while the pathogenic subline consisted mainly of cells expressing Vβ8.3 TCRs. Genomic Southern blot analysis of DNA from the pathogenic subline showed that Vβ8.3-expressing T cells were the dominant clonotype, and DNA sequence analyses of Vβ8.3 cDNAs revealed that two Vβ8.3 TCRs were expressed in the pathogenic subline. One of the Vβ8.3 cDNAs encoded a variable region gene segment identical to previously reported rat Vβ8.3 TCR while the other differed by two amino acids in the second complementarity determining region (CDR2). Taken together with previous data showing overrepresentation of Vβ8-expression in T cell lines that induce EAU, but not in nonuveitogenic T cell lines, our results suggest that Vβ8.3-expressing T cells represent a pathogenic clonotype in IRBP-induced EAU.Clinical Immunology and Immunopathology. -
Article: T cell receptor β-chain usage in experimental autoimmune uveoretinitis
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ABSTRACT: Genomic rearrangements to the T-cell receptor (TCR) Vβ8 gene locus were examined in T cells derived from the lymph nodes of Lewis rats immunized with either S-Antigen or peptides derived from interphotoreceptor retinoid binding protein (IRBP). The cells used in these studies are from T-cell lines that have been selected by several cycles of antigen/IL-2 stimulations, or clones isolated from these lines. No apparent rearrangement of the Vβ8 gene was observed by Southern analysis, suggesting that if indeed there are T cells using Vβ8 gene elements they represent small proportions of the cells in these T-cell lines that induce EAU (uveitogenic T cells) and that the lines may consist of large numbers of clones. On the other hand, we have demonstrated Vβ8 gene expression in uveitogenic T-cell populations by Northern analysis and by polymerase chain reaction (PCR). Although Vβ8 gene transcripts were detectable in pathogenic, but not in non-pathogenic, T-cell lines using a Vβ8 cDNA probe, RNA from pathogenic T cell lines did not hybridize to another probe specific for rat Vβ8.2. Taken together, these results suggest that, unlike the T-cell lines that mediate experimental allergic encephalomyelitis (EAE), some T-cell lines that induce EAU do not predominantly express Vβ8.2 gene but other member(s) of the Vβ8 family.Journal of Autoimmunity.
Top co-authors
Top Journals
Institutions
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2002–2012
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National Institutes of Health
- • Section on Molecular Endocrinology
- • Laboratory of Immunology
Bethesda, MD, USA
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2005
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National Eye Institute
Bethesda, MD, USA
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2004
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National Institute of Allergy and Infectious Diseases
Bethesda, MD, USA
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