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Immunological tolerance is defined as a state of specific non-responsiveness to a particular antigen induced by previous exposure to that same antigen. The mucosal surfaces comprise the upper and lower respiratory tracts, the gastrointestinal tract and the urogenitary tract, and are a major site of antigenic challenge. The immune system associated with the mucosa has the extraordinary potential to discriminate between antigens that are harmless (e.g. inhaled and dietary antigens) and those that are associated with pathogens. Normally soluble proteins delivered through the mucosal surfaces do not elicit a strong systemic immune response but instead induce a transient local immune response that is replaced by long-term peripheral unresponsiveness – this is termed mucosal tolerance. The phenomenon of oral tolerance is well established and considerable attention has focussed on defining the underlying mechanisms. However, only comparatively recently was the induction of tolerance via the respiratory mucosa described, and it is this form of mucosal tolerance which forms the basis of this review. [ABSTRACT FROM AUTHOR]

Sonic hedgehog (Shh) is important in the growth and differentiation of a variety of cell types, including the development of T cells in the thymus. This prompted us to investigate whether Shh signaling is a functional component of the physiological response of human mature CD4(+) T cells following Ag recognition. In this study, we demonstrate that Shh and its receptor Patched (Ptc) are expressed on resting and activated human peripheral CD4(+) T cells. In approximately one-half of the randomly selected, anonymous blood donors tested, exposure of anti-CD3/28 Ab-activated CD4(+) T cells to the biologically active N-terminal Shh peptide increased the transcription of ptc, thereby demonstrating that Shh signaling had occurred. Furthermore, the addition of exogenous Shh amplified the production of IL-2, IFN-gamma, and IL-10 by activated CD4(+) T cells. The synthesis of IL-2 and IFN-gamma, but not IL-10, by CD4(+) T cells was down-regulated by the addition of neutralizing anti-Shh Ab. Cell surface expression of CD25 and CD69 on activated T cells was up-regulated by exogenous Shh, whereas in the presence of the neutralizing anti-Shh Ab expression it was reduced. Collectively, our findings demonstrate that Shh-mediated signaling is a physiological component of T cell responses, which acts to modulate CD4(+) T cell effector function.