Diversity of the Human Allergen-Specific T Cell Repertoire Associated with Distinct Skin Test Reactions: Delayed-Type Hypersensitivity-Associated Major Epitopes Induce Th1- and Th2-Dominated Responses

Abstract

Distinct immune responses in humans to the Trichophyton rubrum Ag, Tri r 2, are associated with different patterns of T cell epitope recognition based on in vitro proliferation to peptides derived from this 29-kDa protein. Specifically, the amino-terminal immunodominant epitope, peptide 5 (P5), stimulates strong T cell proliferative responses in subjects with delayed (DTH), but not immediate (IH) hypersensitivity skin tests. Evidence of a role for cytokines or changes in epitope recognition over time was examined in responses to Trichophyton using primary PBMC cultures established from seven IH and seven DTH subjects. Responses stimulated by Tri r 2 were dominated by the Th1 cytokine IFN-γ (IFN-γ:IL-5 ≥ 4:1) in five DTH subjects, even in the presence of Th2-dominated responses (IFN-γ:IL-5 ≤ 3:1) to a subset of major epitopes. Paradoxically, P5 induced IL-5 and IL-10 production in DTH, but not IH subjects (p = 0.003 (IL-5), p = 0.024 (IL-10)), with no significant difference in IFN-γ levels between the two groups. In cultures from IH responders, no IL-5 was measurable after stimulation with P6 and P7 (as well as P5); this region of the molecule was shown previously to stimulate markedly reduced T cell proliferation in these individuals. Repeat proliferation assays confirmed no change in the pattern of peptide recognition after ≥20 mo in IH or DTH subjects. We conclude that T cell repertoires associated with distinct immune responses to Tri r 2 can be distinguished based on Th2 cytokine induction by DTH-associated major epitopes localizing to the amino-terminal region of the molecule.

A Role for IL-10-Mediated HLA-DR7-Restricted T Cell-Dependent Events in Development of the Modified Th2 Response to Cat Allergen

“…These data highlight the importance of analyzing allergen-and epitope-specific responses in parallel in individuals with defined HLA haplotypes (27,53). Although Fel d 1 stimulated reduced IL-10 in PBMC from modified responders (Fig.…”

Skin reactions to human papillomavirus (HPV) 16 specific antigens intradermally injected in healthy subjects and patients with cervical neoplasia

“…Historically, it has been postulated that IFNg-producing Th1 cells induce DTH responses, 14 however, several studies have now shown that both Th1 and Th2 cells are associated with DTH responses and infiltrate the skin test sites. 37,38 Also in our study, the skin test sites of the healthy subjects were infiltrated by HPV16-specific CD41 Th1 and Th2 cells as well as CD81 T cells (Figs. 3 and 4), suggesting that the positive skin reactions in cancer patients are the result of circulating HPV16-specific non-Th1 cells.…”

Allergy and Dermatophytes

“…Given that IH skin tests are often associated with chronic infection, this suggests that the humoral response to Trichophyton is less protective. Although immune mechanisms involved in the natural resolution of infection have yet to be resolved, recent findings suggest that T cells with a defined specificity for fungal antigens are critical to DTH (122,124).…”

“…The development of immediate hypersensitivity (IH) versus delayed-type hypersensitivity (DTH) to Trichophyton allergens may be pivotal to the course and severity of skin infection and also to the development of allergic disease. Definition of the molecular characteristics and immunologic properties of newly identified Trichophyton allergens has advanced our understanding of distinct immune responses to this pathogen (25,108,(122)(123)(124)(125). The putative function of Trichophyton allergens in fungal pathogenesis is described based on their sequence identity to known enzymes.…”