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...

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