Repeated exposure of high-IgE-responder Brown Norway (BN) rats to an aerosol of ovalbumin (OVA) once weekly triggered progressively increasing levels of OVA-specific IgG in serum. In contrast, responses in the IgE class were transient, declining from peak titers during the third week to background levels by Week 5, despite continuing aerosol exposure. Subsequent parenteral challenge of these animals revealed a state of antigen- and IgE isotype-specific tolerance. Adoptive transfer of splenocytes or pooled respiratory tract lymph node (RTLN) cells from aerosol-exposed animals to naive rats abrogated subsequent OVA-specific primary IgE responses in the recipients, but did not affect specific IgG responses, and kinetic studies indicated that these suppressor cells arose first in the RTLN. Transfer studies employing individual lymph node groups which constituted the RTLN pool pinpointed the superficial cervical nodes, which drain the uppermost portion of the respiratory tract, as the major source of suppressor cells. Fractionation of cell populations before adoptive transfer employing monoclonal antibodies directed against T-cell markers, defined a population of suppressor cells generated by aerosol exposure which expressed both the W3/13 (pan T-cell) and OX8 (cytotoxic/suppressor T-cell) antigens, but which was negative for the W3/25 (helper T-cell) marker. Analysis of the IgE and IgG responses induced by OVA inhalation was performed employing the ELISA plaque technique, recently developed in this laboratory. These studies revealed the parathymic and posterior mediastinal nodes draining the lower lung, as the major sites of specific IgE and IgG production; smaller numbers of OVA-specific IgG-secreting cells (but none secreting specific IgE) were detected in the nodes draining the upper respiratory tract, while antibody secretion outside the respiratory tract was restricted to comparatively few cells in the spleen. The ELISA plaque assay was also employed to enumerate total numbers of cells secreting the IgE isotype in aerosol-exposed and control rats, employing samples from 10 different lymphoid organs. Approximately 50% of the IgE-secreting cells in these animals were localized in RTLN, as opposed to 25% in gut-associated lymphoid tissues. These data are discussed in relation to the pivotal role of respiratory-tract associated lymphoid tissues in regulation of IgE responses to aeroallergens.