We have identified at least 2 highly promiscuous major histocompatibility complex class II T-cell epitopes in the Fc fragment of IgG that are capable of specifically activating CD4 ؉ CD25 Hi FoxP3 ؉ natural regulatory T cells (nT Regs IntroductionInduction of specific tolerance to self-or to foreign antigens is the goal of therapy for autoimmunity, transplant rejection, and allergy; unresponsiveness is also desirable in the context of therapy with potentially immunogenic autologous proteins (such as factor VIII) and nonautologous proteins (such as botulinum toxin). Until recently, therapeutic tolerance induction relied on broad-spectrum interventions that resulted in widespread effects on immunity, rather than on strategies directed toward restoring a balance between effector immune responses and regulatory immune responses to a specific protein.Natural means of controlling autoimmune responses (natural tolerance) and of inducing tolerance (adaptive tolerance) are known to exist. For example, suppression of inflammation by CD4 ϩ CD25 Hi FoxP3 ϩ natural regulatory T cells (nT Regs ) is an important mechanism of effector T-cell regulation, and may represent one of the critical forms of autoregulatory response to self-antigens. Upon antigen-specific activation through their TCR, nT Regs are able to suppress bystander effector T-cell responses to unrelated antigens by contact-dependent and -independent mechanisms. Adaptive T Reg (aT Reg ) induction is one outcome of a T-regulatory immune response, and sustained tolerance (to grafts, to allergens, and to autologous proteins) probably requires the existence of aT Regs with the same antigen specificity as the self-reactive T cells. 1-3 Adaptive T Regs are also known as induced T Regs (iT Regs ). However, despite extensive efforts and with few exceptions, 4,5 the antigen specificity of nT Regs is still unknown.Natural T Regs may also control immune responses to autologous proteins to which central tolerance may not exist. For example, it has been suggested that T cells need to be rendered tolerant to the variable regions of antibodies that have undergone somatic hypermutation. 6 To date, no natural T Regs that respond to IgG epitopes have been identified nor have adaptive T Regs to hypervariable IgG regions been identified.We scanned the Fc region of IgG for natural T Reg epitopes that may explain (1) tolerance to antibody variable regions and (2) the induction of tolerance to selected antigens after administration of therapeutic immunoglobulins or Ig fusion proteins. 7,8 Using peripheral blood mononuclear cells (PBMCs) from individuals allergic to either house dust mite Dermatophagoides pteronyssinus (HDM) or to the major birch tree allergen, Bet v 1 141-155 , we evaluated the effect of these IgG T Reg epitopes ("Tregitopes") in a standard 2-step "bystander suppression" assay. We explored whether the Tregitopes induced aT Reg to Bet v 1 141-155 using HLA DR*1501 tetramers to the Bet v 1 141-155 epitope. We also coadministered HDM lysate and Tregitopes to HLA transge...
Sublingual immunotherapy has been shown in some clinical studies to modulate allergen-specific antibody responses [with a decrease in the immunoglobulin E/immunoglobulin G4 (IgE/IgG4) ratio] and to reduce the recruitment and activation of proinflammatory cells in target mucosa. Whereas a central paradigm for successful immunotherapy has been to reorient the pattern of allergen-specific T-cell responses in atopic patients from a T helper (Th)2 to Th1 profile, there is currently a growing interest in eliciting regulatory T cells, capable of downregulating both Th1 and Th2 responses through the production of interleukin (IL)-10 and/or transforming growth factor (TGF)-beta. We discuss herein immune mechanisms involved during allergen-specific sublingual immunotherapy (SLIT), in comparison with subcutaneous immunotherapy. During SLIT, the allergen is captured within the oral mucosa by Langerhans-like dendritic cells expressing high-affinity IgE receptors, producing IL-10 and TGF-beta, and upregulating indoleamine dioxygenase (IDO), suggesting that such cells are prone to induce tolerance. The oral mucosa contains limited number of proinflammatory cells, such as mast cells, thereby explaining the well-established safety profile of SLIT. In this context, second-generation vaccines based on recombinant allergens in a native conformation formulated with adjuvants are designed to target Langerhans-like cells in the sublingual mucosa, with the aim to induce allergen-specific regulatory T cells. Importantly, such recombinant vaccines should facilitate the identification of biological markers of SLIT efficacy in humans.
In this study, we used HLA-DRB1*0101, DRB1*0401, and DRB1*1501 peptide tetramers combined with cytokine surface capture assays to characterize CD4+ T cell responses against the immunodominant T cell epitope (peptide 141–155) from the major birch pollen allergen Bet v 1, in both healthy and allergic individuals. We could detect Bet v 1-specific T cells in the PBMC of 20 birch pollen allergic patients, but also in 9 of 9 healthy individuals tested. Analysis at a single-cell level revealed that allergen-specific CD4+ T cells from healthy individuals secrete IFN-γ and IL-10 in response to the allergen, whereas cells from allergic patients are bona fide Th2 cells (producing mostly IL-5, some IL-10, but no IFN-γ), as corroborated by patterns of cytokines produced by T cell clones. A fraction of Bet v 1-specific cells isolated from healthy, but not allergic, individuals also expresses CTLA-4, glucocorticoid-induced TNF receptor, and Foxp 3, indicating that they represent regulatory T cells. In this model of seasonal exposure to allergen, we also demonstrate the tremendous dynamics of T cell responses in both allergic and nonallergic individuals during the peak pollen season, with an expansion of Bet v 1-specific precursors from 10−6 to 10−3 among circulating CD4+ T lymphocytes. Allergy vaccines should be designed to recapitulate such naturally protective Th1/regulatory T cell responses observed in healthy individuals.
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