Cellular Detection of Human Class II Antigens: Delineation of a Novel HLA-DP-like Suppressor Restriction System DY, the Sequential Expression of Class II Antigens, and a Pronounced Functional Flexibility of Class II Alloproliferative T Cell Clones

Wernet, Peter; Pawelec, Graham; Schneider, E. M.

doi:10.1007/978-3-642-70367-6_16

Cited by 6 publications

(7 citation statements)

References 73 publications

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“…This peculiarly broad reactivity was not due to lack of monoclonality of the test reagents, because Southern blotting of their DNA with TCR-S and -y chain probes indicated monoclonal rearrangements of these genes (27). Such clones appeared to be similar to most DR-, DQ-, or DP-specific PLT clones in that they were CD4+ and secreted IL-2, but they differed in that they exerted strong suppressive activity on LP responses (14,16). Although it is thought unlikely that the suppressive activity could be due to cytotoxic effects, because these TCC showed no killing of sensitive target cells even in the presence of PHA and IL-2 ("liable IV), it cannot be completely excluded that selective cytotoxicity on a minor population such as dendritic cells might contribute to inhibition of LP responses.…”

Section: Discussionmentioning

confidence: 94%

“…B-LCL used as stimulators had been shown by FACS analysis to bind strongly the mAbs used in the blocking experiments, although the level of expression of DQ and DP antigens was almost always lower than that of DR antigens (data not shown) . TO mAbs (13,14,(17)(18)(19)(20) were used as tissue culture supernatants (25%, 1-3 ttg/ml), other mAbs as a 1 :100 dilution of ascites. Additional mAbs used were as follows: L243 (6), Q2/70 (18,20), and SG157 (18) specific for HLA-DR (although Q2/70 may also bind DQ, reference 20); SPV-L3 (4) and Leu10 (18) specific for DQw and DQw1,3 molecules, respectively ; B7/21, specific for HLA-DP (5,15); and PL5 (6), DA6.231 (6,18), and SG520 (6, 18) "broadly" reactive with multiple class II molecules.…”

Section: Methodsmentioning

confidence: 99%

“…similar rationale we previously reported (16) apparently novel lymphocyteactivating determinants (LADS) showing little polymorphism in the population, whose stimulation could be blocked by mAb TU39, but not by a number of other less broadly reactive class II-specific mAbs. These LADS have been operationally designated DY (14). The CD4' cloned lines responding to DY LADs exhibited weak and poorly biphasic proliferative responses not associated with the presence of any identifiable HLA specificity on the stimulating cells (16).…”

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confidence: 99%

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DY determinants, possibly associated with novel class II molecules, stimulate autoreactive CD4+ T cells with suppressive activity.

Pawelec¹,

Fernández²,

Brocker³

et al. 1988

The Journal of Experimental Medicine

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A set of T cell clones (TCC) isolated from HLA-DR-, Dw-, DQ-matched allogeneic MLCs was found to proliferate autonomously when stimulated with cells carrying a wide range of class I or II specificities. This apparently unrestricted proliferation was relatively weak, and only low levels of IL-2 were present in the supernatants of stimulated cells. Autologous as well as allogeneic PBMC and B lymphoblastoid cell lines (B-LCL) were capable of stimulating such clones, which were also restimulated by suppressive, but not by helper, TCC. Moreover, such clones displayed the unusual property of autostimulation. mAb inhibition experiments suggested that class II- or class II-restricted antigens were involved in stimulation. Thus, certain "broad" mAbs (TU39, SG520) reacting with multiple locus products inhibited activation of these reagents, but none of those reacting more specifically with DR (TU34, TU37, L243, Q2/70, SG157), DQ (TU22, SPV-L3, Leu 10), or DP (B7/21), or mixtures of these mAbs, were able to do so. Evidence from sequential immunoprecipitation experiments suggested that mAb TU39 bound class II-like molecules other than DR, DQ, and DP on TCC and B-LCL, and it is therefore proposed that such putative novel class II-like molecules may carry the stimulating determinants for these autoreactive clones. DY-reactive clones lacked helper activity for B cells but mediated potent suppressive activity on T cell proliferative responses that was not restricted by the HLA type of the responding cells. Suppressive activity was induced in normal PBMC by such clones, as well as by independent suppressive clones, which was also inhibited only by mAb TU39. These findings lead to the proposal that DY-reactive autostimulatory cells may constitute a self-maintaining suppressive circuit, the level of activity of which would be regulated primarily by the availability of IL-2 in the microenvironment.

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Section: Discussionmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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DY determinants, possibly associated with novel class II molecules, stimulate autoreactive CD4+ T cells with suppressive activity.

Pawelec¹,

Fernández²,

Brocker³

et al. 1988

The Journal of Experimental Medicine

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“…This reagent has been demonstrated to block antigen presentation restricted by HLA-DR at the concentration applied (320 g/ml) (20). This reagent has been demonstrated to block antigen presentation restricted by HLA-DR at the concentration applied (320 g/ml) (20).…”

Section: Methodsmentioning

confidence: 99%

p205 is a major target of autoreactive T cells in rheumatoid arthritis

Bläß

Schumann

Hain

et al. 1999

Arthritis & Rheumatism

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Objective. The p205 autoantigen and interleukin-2 (IL-2) function synergistically to stimulate T lymphocytes from patients with rheumatoid arthritis (RA), and a p205-derived amino acid sequence is identical to an immunoglobulin sequence located within a domain that is reactive with rheumatoid factors (RF). This study was conducted to analyze in detail the T cell immune response against p205 and to investigate whether immunity to p205 may play a role in T cell-mediated immunopathology in active RA. Methods. Cibachron blue, protein A-Sepharose, and gel filtration on Sephacryl were used successively to enrich p205 from synovial fluid (SF). T lymphocytes from RA patients were isolated from the peripheral blood (PB), lymph nodes, and SF, and p205 and pep-tides derived from known sequences were assessed by T cell proliferation assays in the presence of IL-2. Results. P205-specific proliferation of T cells was observed in PB as well as in SF. When p205 was isolated from RA SF, proliferation of RA T cells peaked on day 3. With p205 purified from SF from trauma patients, there was a significant shift of the maximum T cell proliferation to day 8. T cells were of CD4 or CD8 phenotype, and B cells did not proliferate to a significant degree. The T cell response to p205 was always higher for SF mononuclear cells (SFMC) compared with PBMC (P < < < 0.001). In 1 RA patient who underwent repeated leukapheresis, this led to a reproducible decline in p205-specific T cell proliferation to control levels. PB T cells specifically proliferating in response to p205 were detected in 20 of 32 RA patients (63%). Of 26 patients with other inflammatory rheumatic diseases, only 1 showed a minor response to p205, while normal donors did not demonstrate a significant T cell proliferation. A synthetic p205-derived peptide, with an amino acid sequence identical to an immunoglobulin sequence located in the area where RF binds, was reactive with T cells from RA patients. Conclusion. P205 appears to be a major target of autoreactive T cells in RA. P205-specific T cells are primed and more abundant at the site of inflammation. As a T cell target in RA, p205 may well be an antigen involved in the initiation of RF production.

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“…These reagents block antigen presentation that is restricted by HLA-DR, DP, or DQ, respectively, at the concentrations applied (320 g/ml) (23)(24)(25)(26). These reagents block antigen presentation that is restricted by HLA-DR, DP, or DQ, respectively, at the concentrations applied (320 g/ml) (23)(24)(25)(26).…”

Section: Methodsmentioning

confidence: 99%

The stress protein BiP is overexpressed and is a major B and T cell target in rheumatoid arthritis

Bläß¹,

Union²,

Raymackers³

et al. 2001

Arthritis & Rheumatism

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Objective. The ubiquitously expressed intracellular protein formerly designated p68 has been identified as autoantigen at both the antibody and the T cell level in rheumatoid arthritis (RA).Methods. We used 2 independent approaches, Edman degradation and matrix-assisted laser desorption ionization-time-of-flight mass spectrometry, to characterize p68, and we compared its features with those of the endoplasmic reticulum stress protein BiP.Results. In synovial sections from RA patients, BiP was highly overexpressed as compared with control sections. Under in vitro stress conditions, BiP was found to translocate to the nucleus and the cell surface. BiP-specific autoantibodies were present in 63% of 400 RA patients, in 7% of 200 patients with other rheumatic diseases, and in none of the healthy subjects. Thus, BiP-specific autoantibodies represent a new diagnostic marker in RA. Furthermore, we found that BiP-specific T cell reactivity was altered in RA. In healthy individuals and patients with other rheumatic diseases, BiPreactive T cells were undetectable. In RA, overt T cell reactivity to BiP was observed or could be induced by specifically blocking antigen presentation to potentially regulatory T cells. Conclusion. Since overexpression of BiP has been shown to decrease the sensitivity of cells to killing bySupported by grants from the Deutsche Forschungsgemeinschaft (SFB 421, C6) and the Bundesministerium für Bildung und Forschung (01 GI 9945, TP C-2.3). 761 762 BLÄ ß ET AL

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Cellular Detection of Human Class II Antigens: Delineation of a Novel HLA-DP-like Suppressor Restriction System DY, the Sequential Expression of Class II Antigens, and a Pronounced Functional Flexibility of Class II Alloproliferative T Cell Clones

Cited by 6 publications

References 73 publications

DY determinants, possibly associated with novel class II molecules, stimulate autoreactive CD4+ T cells with suppressive activity.

DY determinants, possibly associated with novel class II molecules, stimulate autoreactive CD4+ T cells with suppressive activity.

p205 is a major target of autoreactive T cells in rheumatoid arthritis

The stress protein BiP is overexpressed and is a major B and T cell target in rheumatoid arthritis

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