A malaria T-cell epitope recognized in association with most mouse and human MHC class II molecules

Sinigaglia, Francesco; Guttinger, Maria; Kilgus, J.; Doran, D. M.; Matile, Hugues; Etlinger, Howard M.; Trzeciak, Arnold; Gillessen, Dieter; Pink, J. R. L.

doi:10.1038/336778a0

Cited by 355 publications

(173 citation statements)

References 23 publications

Supporting

Mentioning

162

Contrasting

Order By: Relevance

“…23,24 In addition, immunodominant and promiscuous HLA class II-restricted epitopes have been reported for several pathogens, and their use has been proposed for the design of synthetic vaccines potentially effective in a wide proportion of the general population. [25][26][27][28][29] This approach is complicated in HCV infection by viral variability, because useful T-cell epitopes should also be located within conserved regions of the virus to elicit cross-reactive responses effective against all different HCV strains.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Conserved hepatitis C virus sequences are highly immunogenic for CD4+ T cells: Implications for vaccine development

et al. 1999

View full text Add to dashboard Cite

The HLA class II-restricted T-cell response to hepatitis C virus (HCV) antigens is believed to influence the final outcome of hepatitis C, because it is vigorous in patients who recover from acute hepatitis C, but it is weak in those who develop a chronic infection. For this reason, exogenous stimulation of T-cell responses in chronic HCV infection may represent a strategy to cure patients with chronic hepatitis C by approximating the vigor of their T-cell reactivity to that of patients who succeed in recovering from hepatitis. It may also be a preventive approach to avoid spread of the virus by facilitating the development of a vigorous protective response at the very early stages of infection. T-cell-based vaccines composed of immunodominant, promiscuous, and conserved T-cell epitopes may represent a powerful tool to achieve optimal stimulation of the T-cell reactivity. To identify HLA class II-restricted T-cell epitopes useful for this purpose, 22 subjects with acute HCV infection were studied and followed for an average time of 29 months. Eight of them recovered from hepatitis, and 14 developed a chronic infection. Overlapping 20-mer peptides covering the entire core and NS4 antigens and a panel of peptides representing highly conserved regions of core, NS3, NS4, and NS5 were used. By direct peripheral blood T-cell stimulation and by finespecificity analysis of HCV-specific T-cell lines and clones, highly immunogenic T-cell epitopes were identified within core, NS3, and NS4. All these epitopes are immunodominant and highly conserved among the known HCV isolates. Moreover, they are promiscuous, because they can be presented to T cells by different HLA class II molecules. Immunodominance, sequence conservation, and promiscuity make these epitopes ideal components of preventive or therapeutic T-cell-based vaccines against HCV. (HEPATOL-OGY 1999;30:1088-1098.)The hepatitis C virus (HCV) is a RNA virus that can cause either acute self-limited infections or, more frequently, chronic liver cell injury leading to cirrhosis and hepatocellular carcinoma in a high proportion of cases. 1 The mechanisms responsible for persistence or viral clearance are still largely unknown. However, recent studies reported different patterns of proliferative T-cell response and cytokine production by antigen-specific CD4 ϩ T cells in patients with self-limited or chronically evolving HCV infection. [2][3][4] Patients with selflimited acute hepatitis show more vigorous peripheral blood proliferative T-cell responses to HCV proteins, predominantly sustained by Th1-like lymphocytes able to secrete proinflammatory cytokines (interferon gamma [IFN-␥] and interleukin-2 [IL-2]). Patients with chronic evolution of infection display weaker and less efficient proliferative T-cell responses suggesting that the intensity of the T-cell reactivity at the early stages of infection may be critical to limit the spread of the virus within the infected host and to keep viral replication under control. 2,3 In continuation of our previous studies suggestin...

show abstract

Section: Discussionmentioning

confidence: 99%

“…3). At least 1 T-cell line from each patient recognized the core sequence [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] showing that the epitope contained within this region is immunodominant for all patients studied (Figs. 1B and 3).…”

Section: Fine Specificity Of the T-cell Response To Core Ns3 Ns4 Amentioning

confidence: 99%

Conserved hepatitis C virus sequences are highly immunogenic for CD4+ T cells: Implications for vaccine development

et al. 1999

View full text Add to dashboard Cite

show abstract

“…Several studies have demonstrated that flanking residues are critical for T cell recognition of some, but not all, clones (84)(85)(86). However, these observations are probably due to differences in TCR-VotVB usage, whereas in the present study,…”

mentioning

confidence: 99%

Amino acid residues that flank core peptide epitopes and the extracellular domains of CD4 modulate differential signaling through the T cell receptor.

Vignali

Strominger

1994

The Journal of Experimental Medicine

View full text Add to dashboard Cite

StlmmaryHen egg lysozyme 52-61-specific CD4 + T cells responded by interleukin 2 (IL-2) secretion to any peptide containing this epitope regardless of length of NH2-and COOH-terminal composition. However, CD4-variants could only respond to peptides containing the two COOHterminal tryptophans at positions 62 and 63. Substitutions at these positions defined patterns of reactivity that were specific for individual T cells inferring a T cell receptor (TCR)-based phenomenon. Thus, the fine specificity of major histocompatibility complex (MHC)-peptide recognition by the TCR was dramatically affected by CD4 and the COOH-terminal peptide composition. Peptides that failed to induce IL-2 secretion in the CD4-variants nevertheless induced strong tyrosine phosphorylation of CD3~'. Thus, whereas the TCR still recognized and bound to the MHC class II-peptide complex resulting in protein phosphorylation, this interaction failed to induce effective signal transduction manifested by IL-2 secretion. This provides a dear example of differential signaling mediated by peptides known to be naturally processed. In addition, the external domains of CD4, rather than its cytoplasmic tail, were critical in aiding TCK recognition of all peptides derived from a single epitope. These data suggest that the nested flanking residues, which are present on MHC class II but not class I bound peptides, are functionally relevant.

show abstract

“…H-2 d and H-2 k mice responded with high titres of antibodies, while in H-2 b , H-2 q and H-2 s , the responses were lower or absent [4]. Such immunological unresponsiveness in mice may be partially circumvented by coupling the antigen to protein carriers [5] or by inserting promiscuous T-cell epitopes [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Breaking the Non‐Responsiveness of C57BL/6 Mice to the Malarial Antigen EB200 – The Role of Carrier and Adjuvant Molecules

et al. 2003

View full text Add to dashboard Cite

Poor immunogenicity and major histocompatibility complex (MHC) restriction of immune responses to certain recombinant proteins or synthetic peptides impose problems in developing effective vaccines. EB200 is one of the vaccine candidate antigens from Plasmodium falciparum, which induces MHC-restricted immune responses in mice of different haplotypes. A way of overcoming this problem is to conjugate the antigen to an immunogenic protein carrier and to use optimal adjuvant substances. We have investigated the carrier effect of glutathione-S-transferase (GST) in CBA and C57BL/6 mice which are high and low responder to EB200, respectively. Our results reveal that the MHC restriction in C57BL/6 mice was broken by the use of GST as a carrier. Studies on the B-cell repertoires in both strains of mice immunized with GST-EB200 by preparing hybridoma cell lines indicate that the B-cell repertoires were similar in both CBA and C57BL/6 mice. However, the antibody affinity and the magnitude of the response were still lower in the low-responder C57BL/6 mice compared with that in CBA even when cholera toxin (CT) was used as adjuvant. To improve the response, the efficacy of various adjuvant substances like alum and Hsp 70 from Trypanosoma cruzi and the combination of various adjuvants was analysed. CT and Hsp 70 together act synergistically and markedly improve the immunogenicity of EB200 by increasing antibody affinity and the magnitude of the responses in C57BL/6 mice, which may be explained by the complementary effect of adjuvants. These results are of importance in the design of efficient vaccines.

show abstract

A malaria T-cell epitope recognized in association with most mouse and human MHC class II molecules

Cited by 355 publications

References 23 publications

Conserved hepatitis C virus sequences are highly immunogenic for CD4+ T cells: Implications for vaccine development

Conserved hepatitis C virus sequences are highly immunogenic for CD4+ T cells: Implications for vaccine development

Amino acid residues that flank core peptide epitopes and the extracellular domains of CD4 modulate differential signaling through the T cell receptor.

Breaking the Non‐Responsiveness of C57BL/6 Mice to the Malarial Antigen EB200 – The Role of Carrier and Adjuvant Molecules

Contact Info

Product

Resources

About