Structural Analysis of TCRα and β Chains from Human T‐Cell Clones Specific for Small Nuclear Ribonucleoprotein Polypeptides Sm‐D, Sm‐B and U1–70 kDa: TCR Complementarity Determining Region 3 Usage Appears Highly Conserved

Talken, Beth L.; Bailey, Craig W.; Reardon, S. L.; Caldwell, Charles W.; Hoffman, Robert W.

doi:10.1046/j.1365-3083.2001.00930.x

Cited by 20 publications

(27 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with our previous results describing highly restricted complimentarity-determining region 3 usage by anti-U1-70kDa clones, a limited number of T cell epitopes were observed in the anti-U1-70kDa response (14). Remarkably, this response was exclusively limited to epitopes within the RBD of the molecule (residues 92-202), consistent with results previously reported in an animal model of systemic autoimmunity.…”

Section: Discussionsupporting

confidence: 92%

“…We also reported that U1-70kDa-reactive T cells have a typical Th phenotype and produce cytokines that are important in B cell help and differentiation, including IFN-␥, IL-4, and IL-2 (13). Additionally, we have shown that TCR usage by U1-70kDa reactive T cells is highly restricted and by analysis of complimentarity-determining region 3 deduced amino acid sequences found a pattern characteristic of an Ag-driven immune response (14). Finally, in the MRL/Mp-lpr murine model of lupus, we have found that tolerization with a U1-70kDa fusion protein delayed the development of anti-snRNP Abs (15).…”

mentioning

confidence: 64%

“…Control unconjugated maltose-binding protein (MBP), U1-70kDa-MBP fusion protein, and C-terminal truncated forms of U1-70kDa-MBP fusion protein were expressed from the pMAL plasmid in Escherichia coli and affinity purified over amylose columns as previously described (14). For some experiments, forms of U1-70kDa-MBP were further purified by elution of the relevant band cut from 10% SDS-PAGE preparative gels as previously described (26).…”

Section: Recombinant Agmentioning

confidence: 99%

See 2 more Smart Citations

T Cell Immunity in Connective Tissue Disease Patients Targets the RNA Binding Domain of the U1-70kDa Small Nuclear Ribonucleoprotein

Greidinger

Foecking

Schäfermeyer

et al. 2002

The Journal of Immunology

View full text Add to dashboard Cite

Although the T cell dependence of autoimmune responses in connective tissue diseases has been well established, limited information exists regarding the T cell targeting of self Ags in humans. To characterize the T cell response to a connective tissue disease-associated autoantigen, this study generated T cell clones from patients using a set of peptides encompassing the entire linear sequence of the 70-kDa subunit of U1 snRNP (U1-70kDa) small nuclear ribonucleoprotein. Despite the ability of U1-70kDa to undergo multiple forms of Ag modification that have been correlated with distinct clinical disease phenotypes, a remarkably limited and consistent pattern of T cell targeting of U1-70kDa was observed. All tested T cell clones generated against U1-70kDa were specific for epitopes within the RNA binding domain (RBD) of the protein. High avidity binding of the RBD with U1-RNA was preserved with the disease-associated modified forms of U1-70kDa tested. The high avidity interaction between the U1-RBD on the polypeptide and U1-RNA may be critical in immune targeting of this region in autoimmunity. The T cell autoimmune response to U1-70kDa appears to have less diversity than is seen in the humoral response; and therefore, may be a favorable target for therapeutic intervention.

show abstract

Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 64%

Section: Recombinant Agmentioning

confidence: 99%

See 1 more Smart Citation

T Cell Immunity in Connective Tissue Disease Patients Targets the RNA Binding Domain of the U1-70kDa Small Nuclear Ribonucleoprotein

Greidinger

Foecking

Schäfermeyer

et al. 2002

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Defining whether a restricted or a broad family of TCRs is implicated in this mechanism will be also highly informative, because apparently there is an important difference between murine and human lupus with regard to the recognition of peptide P140 by CD4 ϩ T cells. It will be interesting to compare the data with those obtained with U1-70K protein-reactive human T cell clones, the TCR CDR3 of which have been sequenced and found to be highly conserved (37).…”

Section: Discussionmentioning

confidence: 99%

Selective Modulation of CD4+ T Cells from Lupus Patients by a Promiscuous, Protective Peptide Analog

Monneaux

Hoebeke

Sordet

et al. 2005

The Journal of Immunology

View full text Add to dashboard Cite

A peptide encompassing residues 131–151 of the spliceosomal U1-70K protein and its analog phosphorylated at Ser140 were synthesized as potential candidates for the treatment of patients with lupus. Studies in the MRL/lpr and (NZB × NZW)F1 lupus models have demonstrated that these sequences contain a CD4+ T cell epitope but administration of the phosphorylated peptide only ameliorates the clinical manifestations of treated MRL/lpr mice. Binding assays with soluble HLA class II molecules and molecular modeling experiments indicate that both peptides behave as promiscuous epitopes and bind to a large panel of human DR molecules. In contrast to normal T cells and T cells from non-lupus autoimmune patients, we found that PBMCs from 40% of lupus patients selected randomly and CFSE-labeled CD4+ T cells proliferate in response to peptide 131–151. Remarkably, however, we observed that phosphorylation of Ser140 prevents CD4+ T cells proliferation but not secretion of regulatory cytokines, suggesting a striking immunomodulatory effect of phosphorylated analog on lupus CD4+ T cells that was unique to patients. The analog might act as an activator of regulatory T cells or as a partial agonist of TCR.

show abstract

“…Both can help B cells to produce autoantibody but their role in effecting organ injury is not well understood. It appears that certain T cell clonotypes are involved in this process [12], suggesting strongly that limited autoantigens are responsible for the initiation of the autoimmune process. The ability of expanded T helper cells able to provide help to B cells has been exploited in clinical trials where the CD40-CD40 ligand cognate B-T cell interaction is disrupted with appropriate biologics [13].…”

mentioning

confidence: 99%

Drugs, sun and T cells in lupus

Tsokos

2004

Clinical and Experimental Immunology

View full text Add to dashboard Cite

That T cells are central in the expression of systemic autoimmunity as it relates to systemic lupus erythematosus (SLE) is well established [1,2]; treatment of lupus-prone mice with anti-T cell antibodies limits systemic disease [3,4] and, in humans, T cells are also central in the development of disease [2]. SLE T cells display a number of biochemical aberrations [5] that underwrite a T cell receptor (TCR) overexcitable phenotype [6,7] and lower excitation threshold to antigen [8,9] and presumably to autoantigen.Various T cell subsets are involved including TCR ab positive [10] and TCR gd positive [11] subsets. Both can help B cells to produce autoantibody but their role in effecting organ injury is not well understood. It appears that certain T cell clonotypes are involved in this process [12], suggesting strongly that limited autoantigens are responsible for the initiation of the autoimmune process. The ability of expanded T helper cells able to provide help to B cells has been exploited in clinical trials where the CD40-CD40 ligand cognate B-T cell interaction is disrupted with appropriate biologics [13].There is an important unanswered question: if autoantibodies and immune complexes are not responsible for all end organ damage then to what extent are T cells directly involved?TCR a -/ -MRL mice develop disease characterized by increased mortality, overt renal disease and skin lesions. While delayed in onset and/or reduced in severity, compared with TCR a +/+ MRL/ lpr animals, renal and skin lesions in TCR ab T cell-deficient animals are clearly increased in severity compared with agematched control non-autoimmune mice. The TCR a -deficient MRL/lpr mice displayed a predominantly IgG1 immune complex deposition, with poor complement fixation [14]. Therefore, systemic autoimmunity can be dissociated at least partially from skin and possibly renal disease and, therefore, the factors that are involved deserve special study. A study published in this issue [15] indicates that lack of TCR ab in a non-autoimmune murine background can facilitate fluorouracil and ultraviolet light-instigated skin lesions. The study is preliminary in many ways, as it is not indicated whether the lack of TCR a cells or the inadvertent expansion of other subsets is responsible for the skin disease. Transfer of gd T cells did not alter the appearance skin lesions, but the cell transfer experiment was not designed to address the role of these cells. Fluorouracil and ultraviolet light can damage skin cells and redistribute the localization of cellular antigens to surface blebs and henceforth stimulate a local and systemic immune response [16].Evidence suggests that the regulation of systemic autoimmune disease does not depend solely on the initial activation of autoreactive cells in lymphoid organs but also on factors related to the target organ. A recent study reported an interesting dissociation of target organ disease in b 2-microglobulin-deficient MRL/lpr mice: lupus skin lesions were accelerated, whereas nephritis was ameliorated [17]...

show abstract

Structural Analysis of TCRα and β Chains from Human T‐Cell Clones Specific for Small Nuclear Ribonucleoprotein Polypeptides Sm‐D, Sm‐B and U1–70 kDa: TCR Complementarity Determining Region 3 Usage Appears Highly Conserved

Cited by 20 publications

References 31 publications

T Cell Immunity in Connective Tissue Disease Patients Targets the RNA Binding Domain of the U1-70kDa Small Nuclear Ribonucleoprotein

T Cell Immunity in Connective Tissue Disease Patients Targets the RNA Binding Domain of the U1-70kDa Small Nuclear Ribonucleoprotein

Selective Modulation of CD4+ T Cells from Lupus Patients by a Promiscuous, Protective Peptide Analog

Drugs, sun and T cells in lupus

Contact Info

Product

Resources

About