Respiratory exposure to allergen induces T cell tolerance and protection against the development of airway hyperreactivity and asthma. However, the specific mechanisms by which tolerance is induced by respiratory allergen are not clear. We report here that pulmonary dendritic cells (DCs) from mice exposed to respiratory antigen transiently produced interleukin 10 (IL-10). These phenotypically mature pulmonary DCs, which were B-7(hi) as well as producing IL-10, stimulated the development of CD4(+) T regulatory 1--like cells that also produced high amounts of IL-10. In addition, adoptive transfer of pulmonary DCs from IL-10(+/+), but not IL-10(-/-), mice exposed to respiratory antigen induced antigen-specific unresponsiveness in recipient mice. These studies show that IL-10 production by DCs is critical for the induction of tolerance, and that phenotypically mature pulmonary DCs mediate tolerance induced by respiratory exposure to antigen.

Using natural killer T (NKT) cell-deficient mice, we show here that allergen-induced airway hyperreactivity (AHR), a cardinal feature of asthma, does not develop in the absence of V(alpha)14i NKT cells. The failure of NKT cell-deficient mice to develop AHR is not due to an inability of these mice to produce type 2 T-helper (Th2) responses because NKT cell-deficient mice that are immunized subcutaneously at non-mucosal sites produce normal Th2-biased responses. The failure to develop AHR can be reversed by the adoptive transfer of tetramer-purified NKT cells producing interleukin (IL)-4 and IL-13 to Ja281(-/-) mice, which lack the invariant T-cell receptor (TCR) of NKT cells, or by the administration to Cd1d(-/-) mice of recombinant IL-13, which directly affects airway smooth muscle cells. Thus, pulmonary V(alpha)14i NKT cells crucially regulate the development of asthma and Th2-biased respiratory immunity against nominal exogenous antigens. Therapies that target V(alpha)14i NKT cells may be clinically effective in limiting the development of AHR and asthma.

Asthma is caused by T-helper cell 2 (Th2)-driven immune responses, but the immunological mechanisms that protect against asthma development are poorly understood. T-cell tolerance, induced by respiratory exposure to allergen, can inhibit the development of airway hyperreactivity (AHR), a cardinal feature of asthma, and we show here that regulatory T (T(R)) cells can mediate this protective effect. Mature pulmonary dendritic cells in the bronchial lymph nodes of mice exposed to respiratory allergen induced the development of T(R) cells, in a process that required T-cell costimulation via the inducible costimulator (ICOS-ICOS-ligand pathway. The T(R) cells produced IL-10, and had potent inhibitory activity; when adoptively transferred into sensitized mice, T(R) cells blocked the development of AHR. Both the development and the inhibitory function of regulatory cells were dependent on the presence of IL-10 and on ICOS-ICOS-ligand interactions. These studies demonstrate that T(R) cells and the ICOS-ICOS-ligand signaling pathway are critically involved in respiratory tolerance and in downregulating pulmonary inflammation in asthma.

To simplify the analysis of asthma susceptibility genes located at human chromosome 5q23-35, we examined congenic mice that differed at the homologous chromosomal segment. We identified a Mendelian trait encoded by T cell and Airway Phenotype Regulator (Tapr). Tapr is genetically distinct from known cytokine genes and controls the development of airway hyperreactivity and T cell production of interleukin 4 (IL-4) and IL-13. Positional cloning identified a gene family that encodes T cell membrane proteins (TIMs); major sequence variants of this gene family (Tim) completely cosegregated with Tapr. The human homolog of TIM-1 is the hepatitis A virus (HAV) receptor, which may explain the inverse relationship between HAV infection and the development of atopy.

The remarkable increase in asthma prevalence that has occurred over the last two decades is thought to be caused by changes in the environment due to improved hygiene and fewer childhood infections. However, the specific infections that limit T helper type 2 (T(H)2)-biased inflammation and asthma are not fully known. Infectious organisms, including commensal bacteria in the gastrointestinal tract and hepatitis A virus, may normally induce the development of regulatory T (T(R)) cells and protective immunity that limit airway inflammation and promote tolerance to respiratory allergens. In the absence of such infections, T(H)2 cells--which are developmentally related to T(R) cells--develop instead and coordinate the development of asthmatic inflammation.