B Wu

CD4+CD25+ T Cells Lyse Antigen-Presenting B Cells by Fas-Fas Ligand Interaction in an Epitope-Specific Manner

Suppression by regulatory T cells is now acknowledged to play a key role in the down-regulation of T cell responses to foreign and self Ags. In addition to the naturally occurring CD4+CD25+ population, several subtypes of induced regulatory cells have been reported, but their mechanisms of action remain unclear. Conversely, cytotoxic CD4+ cells that lyse cells presenting their cognate peptide have been described, but their potential role in immunoregulation remains to be delineated. A CD4+ T cell line derived from BALB/c mice immunized with peptide 21–35, containing a major T cell epitope of a common allergen, Dermatophagoides pteronyssinus group 2 allergen, was found to lyse the Ag-presenting WEHI cell line via Fas-Fas ligand and only in the presence of the cognate peptide. Cytolytic activity was likewise shown for other T cell lines and occurred even after a single cycle of in vitro stimulation. Moreover, T cells that efficiently lysed WEHI cells were unresponsive to stimulation with their cognate Ag and were dependent on IL-2 for growth and survival, which was reflected in a constitutive expression of CD25 independently of activation status. Proliferating B cells were also killed by the CTLs. By lysing Ag-presenting B cells in an epitope-specific manner, the nonproliferating CTLs were shown to down-regulate the proliferation of bystander T cells. These data demonstrate that cytotoxic CD4+CD25+ T cells that lack proliferation capacities have the potential to down-regulate an immune response by killing Ag-presenting B cells. This could represent an important and specific down-regulatory mechanism of secondary immune responses in vivo.

Major T cell epitope-containing peptides can elicit strong antibody responses

Peptides containing major T cell epitopes have the capacity to induce T cell anergy and have therefore been proposed for the treatment of allergic and autoimmune diseases. Such peptides should not be immunogenic, i.  e. should not contain a B cell recognition site. We have evaluated in BALB / c mice the therapeutic potential of a 15‐mer peptide (p21 – 35) derived from Der p2, a major allergen of the house dust mite Dermatophagoides pteronyssinus, which contains a dominant T cell epitope but is not recognized by antibodies to Der p2. Unexpectedly, p21 – 35 elicited strong immune responses, suggesting the presence of a cryptic B cell epitope. Similar results were obtained with mice of three additional MHC haplotypes. A core sequence of four amino acids (Ile‐Ile‐His‐Arg) corresponding to residues 28 – 31 was shared by the B and T cell epitopes. Critical residues for B cell recognition were Arg31 and Lys33, while Ile28 was essential for T cell recognition. A Lys33Ala mutant of p21 – 35 still activated T cells but had much reduced immunogenic properties, making it a suitable alternative peptide for T cell anergy induction. Careful investigation of the immunogenic potential of peptides used to induce T cell anergy should be carried out prior to their clinical application.

The Dermatophagoides pteronyssinus Group 2 Allergen Contains a Universally Immunogenic T Cell Epitope

The use of T cell epitope-containing peptides for the induction of anergy in allergen sensitization is limited by genetic restriction that could be circumvented by using universally immunogenic epitopes. We attempted to identify such epitopes on Dermatophagoides pteronyssinus group 2 allergen (Der p 2), a major allergen of D. pteronyssinus T cells from BALB/c (H-2d), C57BL/6 (H-2b), C3H (H-2k), and SJL (H-2s) mice that were immunized with rDer p 2, recognized an immunodominant region encompassing residues 21–35. A synthetic 21–35 peptide (p21–35) induced strong dose-dependent in vitro T cell proliferation with cells of the four mouse strains and required processing for MHC class II presentation. Substitution of Ile28 with Ala resulted in reduction of T cell proliferation in each strain. Ile28 could represent an important MHC class II anchoring residue for T cell response to p21–35. An immunodominant T cell epitope of Der p 2 therefore behaves as a universal epitope and could be a suitable candidate for T cell anergy induction.

A Naturally-Processed Universal T Cell Epitope Is Located Within a Conserved Region of Der p 2: Implications for Allergen Sensitization and Immunotherapy

Background: Major allergens could represent a ‘port of entry’ to allergen polysensitization. The immunogenic properties of Der p 2 T cell epitopes were evaluated to test this hypothesis. Material and Methods: T cells were obtained from regional lymph nodes of mice belonging to four different haplotypes and used in proliferation assays using Der p 2 or synthetic peptides. Results: T cells from recombinant (r) Der p 2-immunized Balb/c mice (H-2d) proliferated to an immunodominant region encompassing residues 21–35, which also stimulates T cells of mice expressing three alternative haplotypes (H-2b, H-2k and H-2s), indicating the presence of a universal T cell epitope. Epitope mapping identified Ile28 as a critical H-2-binding residue for all four different haplotypes. p21–35 presents a sequence homology with FIS, another universal T cell epitope. FIS priming boosts immune responses to distinct weak immunogens. Balb/c mice primed with p21–35 or FIS produced stronger immune responses to transferrin upon administration of the latter than unprimed mice. Besides, this procedure profoundly affected the overall B cell response to rDer p 2. Conclusion: An immunodominant T cell epitope of Der p 2 behaves as a universal epitope and enhances responses to related and unrelated coadministered antigens. These findings have implications for the understanding of allergen polysensitization and for immunotherapy.