Resting small B cells present endogenous immunoglobulin variable-region determinants to idiotope-specific CD4+ T cellsin vivo

Munthe, Ludvig A.; Kyte, Jon Amund; Bogen, Bjarne

doi:10.1002/(sici)1521-4141(199912)29:12<4043::aid-immu4043>3.0.co;2-e

Cited by 49 publications

(51 citation statements)

References 47 publications

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“…Although B cells can drive the expansion of T cells in vivo [44,45] including at the resting state [46,47], our results can be interpreted to suggest that CTL priming is mediated by DC after capture of soluble transgenic Ig or cross-priming. However, because CTL priming was possible in relB -/-BM chimeras, whose spleen DC are unable to prime T cell responses to soluble antigen in vitro and in vivo [22], we argue that DC are dispensable in T cell priming in this model.…”

Section: Discussionmentioning

confidence: 84%

Role of T cell help and endoplasmic reticulum targeting in protective CTL response against influenza virus

et al. 2003

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We report on the induction of primary and long-term memory cytotoxic T lymphocyte (CTL) responses against the nucleoprotein of the influenza virus A/PR8/34 in mice immunized with plasmid DNA targeted to B lymphocytes in the spleen. We found that the magnitude of the CTL response and the size of the pool of memory CTL was greater when the CTL response was induced in presence of T cell help. Interestingly, immunization with a signal sequencecompetent transgene was markedly superior to immunization with a transgene lacking the endoplasmic reticulum (ER) targeting sequence, in inducing CTL. We also found a correlation between in vivo protection from lethal virus challenge and (1) the availability of T cell help and (2) ER targeting. Immunization of dendritic cell-deficient mice suggests that B lymphocytes function as antigen-presenting cells in this model of immunization. Collectively, the results suggest that somatic transgene immunization is a conceptually new approach to induce effective anti-viral CTL responses and to assess the parameters critical for long-lasting and protective CTL responses in vivo.

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Section: Discussionmentioning

confidence: 84%

Role of T cell help and endoplasmic reticulum targeting in protective CTL response against influenza virus

et al. 2003

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“…In somatic transgene immunization, the transgene is productively harbored in splenic B cells (12), making it plausible that B cells are likely to serve as the initial APC to present peptides of the endogenously synthesized Ig heavy (H) chain transgene (25). This position is strengthened by the recent report that resting small B cells are able to present self-idiotype peptides to CD4 T cells in vivo (26). During a T-B interaction, up-regulation of CD40L on T cells begins 3-5 h after recognition of antigen (27).…”

Section: Resultsmentioning

confidence: 99%

Functional cooperation between T helper cell determinants

Gerloni

Xiong

Mukerjee

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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A ssociative recognition is a basic regulatory mechanism of the immune response and refers to the phenomenon in which immunity to one determinant of a multideterminant antigen enhances the response to other determinants. The cooperative effect is mediated by a determinant recognized by T helper cells (Th) and has been demonstrated for B cell responses (T-B cooperation) (1) and cytotoxic T lymphocytes responses (Th-cytotoxic T lymphocyte cooperation) (2). A similar form of associative recognition between two Th cell determinants (Th-Th cooperation) has not been described yet but could prove valuable to responses against poorly immunogenic antigens such as tumor antigens. The immune response against tumor antigens is hindered, among other factors, by down-regulation of MHC molecules, self-tolerance, and functional hierarchy in the immunogenicity of T cell determinants. It is now clear that T cell determinants of protein antigens can be categorized into dominant, subdominant, and cryptic to reflect a different degree of immunogenicity in vivo (3). Consequently, as T cells reactive with dominant determinants of tumor antigens are eliminated in the thymus during negative selection, the adult immune repertoire is composed mainly of precursor cells with moderate avidity for subdominant and cryptic determinants. Thus, methods to heighten the response of CD4 and CD8 T lymphocytes of the residual repertoire against poorly immunogenic determinants are needed to develop better immunogens against cancer.MUC-1, a glycosylated molecule of high molecular weight expressed in malignant tumors of epithelial origin (4, 5), induces both CD8 (6-8) and CD4 T lymphocytes (9, 10) against an antigenic core consisting of a tandem repeat of 20 amino acid residues. For these reasons, MUC-1 is a useful model antigen for targeted manipulations of the immune response. Specific T cell responses against MUC-1 were induced in C57BL͞6 mice using a model of epitope-based genetic vaccination, somatic transgene immunization (11). This approach is based on the inoculation into the spleen of adult mice of plasmid DNA comprising an Ig heavy (H) chain gene controlled by a B cell-specific promoter to target resident B cells (12). The use of Ig genes modified in the complementaritydetermining regions (CDR) to code for heterologous epitopes (13) allows one to direct the in vivo synthesis and secretion by B cells of transgenic Ig, which immunize the host against the B and T cell epitopes expressed in their V region (14,15). Unlike conventional DNA vaccination (16), which induces Th1 responses (17), somatic transgene immunization activates Th0 cells that produce IL-2, IFN-␥, and IL-4 (15). One advantage of somatic transgene immunization is that heterologous epitopes can be assembled on the Ig V region in various assortment and combination to maximize immunogenicity but also to provide easy tools to study the reciprocal regulation between distinct antigenic determinants during the immune response in vivo.Here, we report that an immunologically silent Th cell d...

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“…Resting small splenic B cells were negatively sorted on a FACSVantage (BD Biosciences), as previously described (30). Briefly, splenocytes were stained with a mixture of biotinylated mAb with broad non-B cell specificities detected with streptavidin CyChrome.…”

Section: Sorting Of B Cells DC and Macrophages From Balb/c Spleensmentioning

confidence: 99%

Efficient Delivery of T Cell Epitopes to APC by Use of MHC Class II-Specific Troybodies

Lunde

Western

Rasmussen

et al. 2002

The Journal of Immunology

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A major objective in vaccine development is the design of reagents that give strong, specific T cell responses. We have constructed a series of rAb with specificity for MHC class II (I-E). Each has one of four different class II-restricted T cell epitopes genetically introduced into the first C domain of the H chain. These four epitopes are: 91–101 λ2315, which is presented by I-Ed; 110–120 hemagglutinin (I-Ed); 323–339 OVA (I-Ad); and 46–61 hen egg lysozyme (I-Ak). We denote such APC-specific, epitope-containing Ab “Troybodies.” When mixed with APC, all four class II-specific Troybodies were ∼1,000 times more efficient at inducing specific T cell activation in vitro compared with nontargeting peptide Ab. Furthermore, they were 1,000–10,000 times more efficient than synthetic peptide or native protein. Conventional intracellular processing of the Troybodies was required to load the epitopes onto MHC class II. Different types of professional APC, such as purified B cells, dendritic cells, and macrophages, were equally efficient at processing and presenting the Troybodies. In vivo, class II-specific Troybodies were at least 100 times more efficient at targeting APC and activating TCR-transgenic T cells than were the nontargeting peptide Ab. Furthermore, they were 100–100,000 times more efficient than synthetic peptide or native protein. The study shows that class II-specific Troybodies can deliver a variety of T cell epitopes to professional APC for efficient presentation, in vitro as well as in vivo. Thus, Troybodies may be useful as tools in vaccine development.

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Resting small B cells present endogenous immunoglobulin variable-region determinants to idiotope-specific CD4+ T cellsin vivo

Cited by 49 publications

References 47 publications

Role of T cell help and endoplasmic reticulum targeting in protective CTL response against influenza virus

Role of T cell help and endoplasmic reticulum targeting in protective CTL response against influenza virus

Functional cooperation between T helper cell determinants

Efficient Delivery of T Cell Epitopes to APC by Use of MHC Class II-Specific Troybodies

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