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K M Sivils - One of the best experts on this subject based on the ideXlab platform.

  • Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study
    Genes & Immunity, 2015
    Co-Authors: M Martins, A H Williams, M Comeau, M Marion, J T Ziegler, B I Freedman, J T Merrill, S B Glenn, J A Kelly, K M Sivils
    Abstract:

    A classic T-cell phenotype in systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters T-cell receptor signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247 –SLE association in a large multiethnic population. We typed 44 contiguous CD247 single-nucleotide polymorphisms (SNPs) in 8922 SLE patients and 8077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99 × 10^−4< P

  • Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study
    Genes and immunity, 2015
    Co-Authors: M Martins, A H Williams, J T Ziegler, B I Freedman, J T Merrill, S B Glenn, J A Kelly, Mary E. Comeau, Miranda C. Marion, K M Sivils
    Abstract:

    A classic T-cell phenotype in systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters T-cell receptor signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247-SLE association in a large multiethnic population. We typed 44 contiguous CD247 single-nucleotide polymorphisms (SNPs) in 8922 SLE patients and 8077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99 × 10(-4) < P < 4.15 × 10(-2)), where we further identified a five-marker haplotype (rs12141731-rs2949655-rs16859085-rs12144621-rs858554; G-G-A-G-A; P(hap) = 2.12 × 10(-5)) that exceeded the most associated single SNP rs858554 (minor allele frequency in controls = 13%; P = 4.99 × 10(-4), odds ratio = 1.32) in significance. Imputation and subsequent association analysis showed evidence of association (P < 0.05) at 27 additional SNPs within intron 1. Cross-ethnic meta-analysis, assuming an additive genetic model adjusted for population proportions, showed five SNPs with significant P-values (1.40 × 10(-3) < P< 3.97 × 10(-2)), with one (rs704848) remaining significant after Bonferroni correction (P(meta) = 2.66 × 10(-2)). Our study independently confirms and extends the association of SLE with CD247, which is shared by various autoimmune disorders and supports a common T-cell-mediated mechanism.

Torsten Witte - One of the best experts on this subject based on the ideXlab platform.

  • Association of CD247 polymorphisms with rheumatoid arthritis: a replication study and a meta-analysis.
    PloS one, 2013
    Co-Authors: María Teruel, Cushla Mckinney, Alejandro Balsa, Dora Pascual-salcedo, Luis Rodriguez-rodriguez, Ana M. Ortiz, Carmen Gómez-vaquero, Miguel A. González-gay, Malcolm D. Smith, Torsten Witte
    Abstract:

    Given the role of CD247 in the response of the T cells, its entailment in autoimmune diseases and in order to better clarify the role of this gene in RA susceptibility, we aimed to analyze CD247 gene variants previously associated with other autoimmune diseases (rs1052237, rs2056626 and rs864537) in a large independent European Caucasian population. However, no evidence of association was found for the analyzed CD247 single-nucleotide polymorphisms (SNPs) with RA and with the presence/absence of anti-cyclic citrullinated polypeptide. We performed a meta-analysis including previously published GWAS data from the rs864537 variant, revealing an overall genome-wide significant association between this CD247 SNP and RA with anti-CCP (OR = 0.90, CI 95% = 0.87–0.93, Poverall = 2.1×10−10). Our results show for first time a GWAS-level association between this CD247 polymorphism and RA risk.

  • AB0093 Association of CD247 polymorphisms with rheumatoid arthritis: a replication study and a meta-analysis
    Annals of the Rheumatic Diseases, 2013
    Co-Authors: María Teruel, Cushla Mckinney, Alejandro Balsa, Dora Pascual-salcedo, Luis Rodriguez-rodriguez, Ana M. Ortiz, Carmen Gómez-vaquero, Miguel A. González-gay, Malcolm D. Smith, Torsten Witte
    Abstract:

    Background The T-cell receptor T3 zeta chain ( CD3 ζ), also called CD247, is essential for assembly, surface expression and signaling cascade of the T-cell receptor-CD3 complex (TCR/CD3 complex). Abnormalities in this pathway can result in T-cell dysfunction and development of autoimmune disorders [1]. Regarding this, previous reports have demonstrated an association of CD247 variants with systemic lupus erythematosus [2, 3] and systemic sclerosis [4, 5]. In the case of rheumatoid arthritis (RA), one meta-GWAS found no association between CD247 gene and RA at a genome-wide level of significance [6], however, a more recent meta-analysis of GWAS on RA and celiac disease (CeD) identified CD247 gene as a new susceptibility locus for RA [7]. Objectives In order to better clarify the role of this gene in RA susceptibility, we aimed to analyze CD247 gene variants previously associated with other autoimmune diseases (rs1052237, rs2056626 and rs864537) in a large independent European Caucasian population. Results However, no evidence of association was found for these three CD247 SNPs with RA and with the anti-cyclic citrullinated polypeptide (anti-CCP) status. We performed a meta-analysis including GWAS data for the rs864537 from previously published data, reveling an overall genome-wide significant association between rs864537 and RA with anti-CCP (OR 0.90 [0.87 to 0.93], P overall = 2.1 x 10 -10 ). Conclusions Our results described for first time at GWAS-level the association of this CD247 variant and RA risk References Takeuchi T et al . Ann Rheum Dis . 2012; 71:i78-i81. Gorman CL et al . J Immunol . 2008; 180: 1060-70. Warchol T et al . Tissue Antigens . 2009; 74:68-72. Dieude P et al . Ann Rheum Dis . 2011;70:1695-6. Radstake TR et al . Nat Genet . 2010; 42:426-9. Stahl EA et al . Nat Genet . 2010; 42:508-14. Zhernakova A et al . PLoS Genet . 2011; 7:e1002004. Acknowledgements This work was supported by two Spanish grants from RETICS Program, RD08/0075 (RIER) from Instituto de Salud Carlos III (ISCIII), within the VI PN de I+D+i 2008-2011 (FEDER) and also by grants from the European IMI BTCure Program. MT was supported by Spanish Ministry of Science through the program Juan de la Cierva (JCI-2010-08227). Disclosure of Interest None Declared

M Martins - One of the best experts on this subject based on the ideXlab platform.

  • Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study
    Genes & Immunity, 2015
    Co-Authors: M Martins, A H Williams, M Comeau, M Marion, J T Ziegler, B I Freedman, J T Merrill, S B Glenn, J A Kelly, K M Sivils
    Abstract:

    A classic T-cell phenotype in systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters T-cell receptor signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247 –SLE association in a large multiethnic population. We typed 44 contiguous CD247 single-nucleotide polymorphisms (SNPs) in 8922 SLE patients and 8077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99 × 10^−4< P

  • Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study
    Genes and immunity, 2015
    Co-Authors: M Martins, A H Williams, J T Ziegler, B I Freedman, J T Merrill, S B Glenn, J A Kelly, Mary E. Comeau, Miranda C. Marion, K M Sivils
    Abstract:

    A classic T-cell phenotype in systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters T-cell receptor signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247-SLE association in a large multiethnic population. We typed 44 contiguous CD247 single-nucleotide polymorphisms (SNPs) in 8922 SLE patients and 8077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99 × 10(-4) < P < 4.15 × 10(-2)), where we further identified a five-marker haplotype (rs12141731-rs2949655-rs16859085-rs12144621-rs858554; G-G-A-G-A; P(hap) = 2.12 × 10(-5)) that exceeded the most associated single SNP rs858554 (minor allele frequency in controls = 13%; P = 4.99 × 10(-4), odds ratio = 1.32) in significance. Imputation and subsequent association analysis showed evidence of association (P < 0.05) at 27 additional SNPs within intron 1. Cross-ethnic meta-analysis, assuming an additive genetic model adjusted for population proportions, showed five SNPs with significant P-values (1.40 × 10(-3) < P< 3.97 × 10(-2)), with one (rs704848) remaining significant after Bonferroni correction (P(meta) = 2.66 × 10(-2)). Our study independently confirms and extends the association of SLE with CD247, which is shared by various autoimmune disorders and supports a common T-cell-mediated mechanism.

Michael Bukrinsky - One of the best experts on this subject based on the ideXlab platform.

  • cyclophilin cd147 interactions a new target for anti inflammatory therapeutics
    Clinical and Experimental Immunology, 2010
    Co-Authors: Vyacheslav Yurchenko, Elan Z Eisenmesser, Stephanie L. Constant, Michael Bukrinsky
    Abstract:

    CD147 is a widely expressed plasma membrane protein that has been implicated in a variety of physiological and pathological activities. It is best known for its ability to function as extracellular matrix metalloproteinase inducer (hence the other name for this protein, EMMPRIN), but has also been shown to regulate lymphocyte responsiveness, monocarboxylate transporter expression and spermatogenesis. These functions reflect multiple interacting partners of CD147. Among these CD147-interacting proteins cyclophilins represent a particularly interesting class, both in terms of structural considerations and potential medical implications. CD147 has been shown to function as a signalling receptor for extracellular cyclophilins A and B and to mediate chemotactic activity of cyclophilins towards a variety of immune cells. Recent studies using in vitro and in vivo models have demonstrated a role for cyclophilin-CD147 interactions in the regulation of inflammatory responses in a number of diseases, including acute lung inflammation, rheumatoid arthritis and cardiovascular disease. Agents targeting either CD147 or cyclophilin activity showed significant anti-inflammatory effects in experimental models, suggesting CD147-cyclophilin interactions may be a good target for new anti-inflammatory therapeutics. Here, we review the recent literature on different aspects of cyclophilin-CD147 interactions and their role in inflammatory diseases.

  • Cyclophilin–CD147 interactions: a new target for anti‐inflammatory therapeutics
    Clinical and experimental immunology, 2010
    Co-Authors: Vyacheslav Yurchenko, Elan Z Eisenmesser, Stephanie L. Constant, Michael Bukrinsky
    Abstract:

    CD147 is a widely expressed plasma membrane protein that has been implicated in a variety of physiological and pathological activities. It is best known for its ability to function as extracellular matrix metalloproteinase inducer (hence the other name for this protein, EMMPRIN), but has also been shown to regulate lymphocyte responsiveness, monocarboxylate transporter expression and spermatogenesis. These functions reflect multiple interacting partners of CD147. Among these CD147-interacting proteins cyclophilins represent a particularly interesting class, both in terms of structural considerations and potential medical implications. CD147 has been shown to function as a signalling receptor for extracellular cyclophilins A and B and to mediate chemotactic activity of cyclophilins towards a variety of immune cells. Recent studies using in vitro and in vivo models have demonstrated a role for cyclophilin-CD147 interactions in the regulation of inflammatory responses in a number of diseases, including acute lung inflammation, rheumatoid arthritis and cardiovascular disease. Agents targeting either CD147 or cyclophilin activity showed significant anti-inflammatory effects in experimental models, suggesting CD147-cyclophilin interactions may be a good target for new anti-inflammatory therapeutics. Here, we review the recent literature on different aspects of cyclophilin-CD147 interactions and their role in inflammatory diseases.

  • Dealing with the family: CD147 interactions with cyclophilins
    Immunology, 2006
    Co-Authors: Vyacheslav Yurchenko, Stephanie L. Constant, Michael Bukrinsky
    Abstract:

    CD147 is a widely expressed plasma membrane protein that has been implicated in a variety of physiological and pathological activities. It is best known for its ability to function as extracellular matrix metalloproteinase inducer (hence the other name for this protein, EMMPRIN), but has also been shown to regulate lymphocyte responsiveness, monocarboxylate transporter expression and spermatogenesis. These functions reflect multiple interacting partners of CD147. Recently, interaction of CD147 with proteins of the cyclophilin family has been demonstrated and activity of CD147 as a signalling receptor to extracellular cyclophilins A and B has been shown. Given that extracellular cyclophilins are potent chemotactic agents for various immune cells, further studies of the role of cyclophilin-CD147 interaction in inflammation followed. They demonstrated that agents targeting CD147 or cyclophilin had a significant anti-inflammatory effect in animal models of acute or chronic lung diseases and rheumatoid arthritis. Here, we review the current knowledge about interactions between CD147 and cyclophilins.

  • Cell Surface Expression of CD147/EMMPRIN Is Regulated by Cyclophilin 60
    The Journal of biological chemistry, 2005
    Co-Authors: Tatiana Pushkarsky, Vyacheslav Yurchenko, Barbara Sherry, Christophe Vanpouille, Beda Brichacek, Iosif I. Vaisman, Shigetsugu Hatakeyama, Keiichi I. Nakayama, Michael Bukrinsky
    Abstract:

    CD147, also known as extracellular matrix metalloproteinase inducer, is a regulator of matrix metalloproteinase production and also serves as a signaling receptor for extracellular cyclophilins. Previously, we demonstrated that cell surface expression of CD147 is sensitive to cyclophilin-binding drug cyclosporin A, suggesting involvement of a cyclophilin in the regulation of intracellular transport of CD147. In this report, we identify this cyclophilin as cyclophilin 60 (Cyp60), a distinct member of the cyclophilin family of proteins. CD147 co-immunoprecipitated with Cyp60, and confocal immunofluorescent microscopy revealed intracellular co-localization of Cyp60 and CD147. This interaction with Cyp60 involved proline 211 of CD147, which was shown previously to be critical for interaction between CD147 and another cyclophilin, cyclophilin A, in solution. Mutation of this proline residue abrogated co-immunoprecipitation of CD147 and Cyp60 and reduced surface expression of CD147 on the plasma membrane. Suppression of Cyp60 expression using RNA interference had an effect similar to that of cyclosporin A: reduction of cell surface expression of CD147. These results suggest that Cyp60 plays an important role in the translocation of CD147 to the cell surface. Therefore, Cyp60 may present a novel target for therapeutic interventions in diseases where CD147 functions as a pathogenic factor, such as cancer, human immunodeficiency virus infection, or rheumatoid arthritis.

  • Regulation of CD147 Cell Surface Expression INVOLVEMENT OF THE PROLINE RESIDUE IN THE CD147 TRANSMEMBRANE DOMAIN
    The Journal of biological chemistry, 2005
    Co-Authors: Vyacheslav Yurchenko, Tatiana Pushkarsky, Wei Wei Dai, Barbara Sherry, Michael Bukrinsky
    Abstract:

    Abstract CD147, also known as extracellular matrix metalloproteinase inducer, is a regulator of matrix metalloproteinase production and serves as a signaling receptor for extracellular cyclophilins. Here we demonstrate that the cell surface expression of CD147 is regulated by cyclophilins via the transmembrane domain of CD147. Solution binding experiments demonstrated that the transmembrane domain was both necessary and sufficient for CD147 binding to cyclophilin A (CypA). Treatment with cyclosporin A significantly reduced surface expression of CD147 and of CD8-CD147 fusion protein carrying the extracellular domain of CD8 fused to the transmembrane and cytoplasmic domains of CD147, but did not affect expression of CD8. Peptide binding studies demonstrated specific interaction between CypA and the proline-containing peptide from the CD147 transmembrane domain. Mutation of this proline residue reduced binding of CD147-derived peptides to CypA and also diminished transport of CD147 to the plasma membrane without reducing the total level of CD147 expression. These results suggest involvement of a cyclophilin-related protein in CD147 cell surface expression and provide molecular details for regulation of CD147 trafficking by cyclophilins.

David L. Mattson - One of the best experts on this subject based on the ideXlab platform.

  • Abstract MP42: T Cell Deletion Normalizes Sex Differences Of Blood Pressure But Not Renal Damage In Dahl Salt-sensitive Rats
    Hypertension, 2020
    Co-Authors: Justine M. Abais-battad, Hayley Lund, Daniel J. Fehrenbach, John Henry Dasinger, David L. Mattson
    Abstract:

    The immune system has a clear role in the development of hypertension and renal damage in male Dahl salt-sensitive (SS) rats, but far less is known about this phenotype in females, especially in regard to the contribution of immune-related mechanisms. The current study examined the hypertensive and kidney injury phenotype in response to a 3 week high salt challenge (HS, 4.0% NaCl, AIN-76A) in female versus male SS rats (n>10/group). Measured via radiotelemetry, there was no difference in low salt (LS, 0.4% NaCl) mean arterial pressure (MAP) between females and males (129±2 vs 124±2 mmHg, respectively). However, after 3 weeks of HS, females had a significant attenuation in the development of hypertension compared to males (161±3 vs 177±7 mmHg). This coincided with significantly less renal damage, evident by markedly reduced albuminuria (105±16 vs 183±16 mg/day) and medullary protein cast formation (7.0±0.7 vs 14.6±1.1%) in the females. Assessed via flow cytometry, there were fewer CD45+ total leukocytes (48% reduction), CD3+ T cells (51%), CD45R+ B cells (73%), and CD11b/c+ monocytes/macrophages (47%) in female versus male kidneys. To interrogate the contribution of adaptive immunity, specifically T cells, to the development of this sex difference, the same parameters were investigated in female and male SS CD247-/- rats which lack CD3+ T cells. The absence of functional T cells significantly reduced blood pressure in both females (147±6 vs 161±3 mmHg; SS CD247-/- vs SS) and males (157±8 vs 177±7 mmHg) after 3 weeks of HS, with no statistical difference between female and male SS CD247-/- rats. While a reduction in albuminuria (females: 37±12 vs 105±16 mg/day; males: 88±13 vs 183±16 mg/day, SS CD247-/- vs SS) and medullary protein cast formation (females: 1.8±0.4 vs 7.0±0.7%; males: 9.1±0.7 vs 14.6±1.1%) was observed in SS CD247-/- versus SS rats regardless of sex, there was greater protection from these measures of kidney damage in SS CD247-/- female versus SS CD247-/- males. Together, our data indicate that female SS rats are significantly protected from high salt-induced hypertension and renal disease compared to males rats. The deletion of T cells normalized high salt blood pressure between male and female rats but sex differences in renal damage still persisted.

  • Abstract P332: Role of T-Lymphocytes in the Long-Term Blood Pressure and Renal Disease Effects of Acute Renal Ischemia-Reperfusion Injury
    Hypertension, 2016
    Co-Authors: Bernardo Lopez, Hayley Lund, Galina Petrova, Justine M. Abais-battad, Daniel J. Fehrenbach, David L. Mattson
    Abstract:

    Epidemiological data indicates that acute kidney injury (AKI) is an independent risk factor for the development of hypertension and chronic kidney disease in patients. Previous studies demonstrated that rats develop sodium-dependent hypertension and kidney damage following experimental AKI induced by a renal ischemia-reperfusion (IR) insult; furthermore, these high salt deleterious effects could be blunted by administration of immunosuppressive agents. The present study was performed on Dahl SS (SS) rats and SS rats with a null mutation in the CD247 gene (SS-CD247) leading to depletion of T-lymphocytes in order to specifically examine the role of T cells in this response (n=5-6 rats/group). As assessed by serum creatinine (SCr) levels, no difference was observed in the initial response to IR injury between SS and SS-CD247: SCr increased from 0.44±0.03 to 2.16±0.32 mg/dl in SS rats 24 hours after an initial 30 minute period of renal ischemia and returned to control levels after 8 days of recovery. Moreover, no differences were noted in mean arterial pressure (MAP) or albumin excretion rate (UAlb) between SS and SS-CD247 after 43 days of recovery from IR injury while the rats were maintained on a low salt (0.4% NaCl) diet. When the rats were fed a 4.0% NaCl diet for two weeks, MAP and UAlb significantly increased in the sham SS to 178±9 mmHg and 189±25 mg/day, respectively; values significantly greater than observed in the sham SS-CD247 rats (148±2 mmHg and 87±17 mg/day). As expected, the SS rats recovered from IR injury demonstrated an exaggerated increase in MAP (peaking at 183±2 mmHg) and UAlb (275±54 mg/day) in response to high salt. There was no difference in the number of total CD3+ lymphocytes in the kidneys of IR and sham SS after high salt, though the ratio of CD4+/CD8+ T cells was increased in the IR group. Compared to sham CD247, an exaggerated elevation of MAP (157±9 mmHg) and UAlb (210±32 mg/day) was also observed in the SS-CD247 rats recovered from IR injury, demonstrating enhanced responsiveness following IR injury in animals lacking T cells. These data indicate that T lymphocytes amplify salt-sensitive hypertension and renal damage, but other mechanisms also mediate the salt-sensitive hypertension and renal damage that occurs in animals recovered from IR injury.

  • CD247 Modulates Blood Pressure by Altering T-Lymphocyte Infiltration in the Kidney
    Hypertension (Dallas Tex. : 1979), 2013
    Co-Authors: Nathan P. Rudemiller, Hayley Lund, Howard J. Jacob, Aron M. Geurts, David L. Mattson
    Abstract:

    The CD3 ζ chain ( CD247 ), a gene involved in T-cell signaling, has been shown to associate with blood pressure in human genetic studies. To test the functional role of CD247 in hypertension and renal disease, zinc-finger nucleases targeting CD247 were injected into Dahl salt-sensitive (SS/JrHsdMcwi) embryos. The resulting 11-bp frameshift deletion in exon 1 of CD247 led to a predicted premature stop codon. Western blotting confirmed the absence of CD247 protein in the thymus, and flow cytometry (n=5–9 per group) demonstrated that the mutant rats ( CD247 –/– ) have a >99% reduction in circulating CD3 + T cells compared with littermate controls ( CD247 +/+ ). Studies were performed on age-matched, littermate male, CD247 +/+ and CD247 –/– rats fed a 4.0% NaCl diet for 3 weeks. The infiltration of CD3 + T cells into the kidney after high salt was significantly blunted in CD247 –/– (1.4±0.4×10 5 cells per kidney) when compared with that in the CD247 +/+ (8.7±2.0×10 5 cells per kidney). Accompanying the reduced infiltration of T cells, mean arterial blood pressure was significantly lower in CD247 –/– than in CD247 +/+ (134±1 versus 151±2 mm Hg). As an index of kidney disease, urinary albumin and protein excretion rates were significantly reduced in CD247 –/– (17±1 and 62±2 mg/d, respectively) when compared with that in CD247 +/+ (49±3 and 121±5 mg/d, respectively). Glomerular and renal tubular damage were also attenuated in the CD247 –/– . These studies demonstrate that functional T cells are required for the full development of Dahl salt-sensitive hypertension and indicate that the association between CD247 and hypertension in humans may be related to altered immune cell function.

  • Abstract 4: Genetic Deletion of CD247 in Dahl Salt-Sensitive (SS) Rats Attenuates Hypertension and Renal Damage
    Hypertension, 2012
    Co-Authors: David L. Mattson, Hayley Lund, Aron M. Geurts, Chuanling Guo, Howard J. Jacob
    Abstract:

    The CD3 zeta chain (CD247), a gene involved in T cell signaling, has been demonstrated to associate with hypertension in human genetic studies. Hypertension and renal damage in the Dahl SS rat are associated with an increase in infiltrating T cells in the kidney. There are numerous descriptions of the role of CD247 as a modulator of T cell receptor signaling, but little is known about the role of this gene product in hypertension. To test the functional role of CD247 in hypertension and renal disease, zinc finger nucleases targeting exon 1 were injected into Dahl SS/JrHsdMcwi embryos. The resulting mutation is a 13-bp frameshift deletion of bases 155-167 in exon 1 of CD247 leading to a predicted stop codon within 19 bases of the mutation. Western blotting confirmed the absence of CD247 protein in the thymus, demonstrating a null mutation, and flow cytometry of circulating T and B-cells in wild type (WT) and CD247 null mutant rats (n=5-10/group) demonstrated that the mutants have a significant decrease in CD3+ T-cells (0.04±0.01 vs 4.6±0.5 x 10 7 cells/ml) and increased CD45R+ B-cells (4.1±0.4 vs 1.2±0.2 x 10 7 cells/ml). Studies were then performed on age-matched, male, WT and CD247 null mutant rats fed a 4.0% NaCl diet for three weeks. The infiltration of CD3+ T-cells into the kidney following high salt was significantly blunted in the CD247 mutant rats (1.4±0.4 x 10 5 cells/kidney) compared to the WT (8.7±2.0 x 10 5 cells/kidney). Accompanying the reduced infiltration of T-cells, mean arterial blood pressure was significantly lower in the CD247 null mutant rats than the WT (134±1 vs 151±2 mmHg). As an index of kidney disease, urinary albumin and protein excretion rate were significantly reduced in CD247 null mutants (17±1 and 62±2 mg/day, respectively) compared to WT (49±3 and 121±5 mg/day, respectively). Finally, a histological analysis revealed that the glomerular and tubular damage in the kidneys of the WT rats fed high salt was also attenuated in the CD247 null mutants. This new experimental model provides evidence that T cells are required for the full development of Dahl SS hypertension and indicate that the association between CD247 and hypertension in humans may be related to altered immune cell function. Supported by HL-29587, DK-62803, and RC2-HL101681.