REGULATION OF T-CELL ACTIVATION IN THE LUNG - ALVEOLAR MACROPHAGES INDUCE REVERSIBLE T-CELL ANERGY IN-VITRO ASSOCIATED WITH INHIBITION OF INTERLEUKIN-2 RECEPTOR SIGNAL-TRANSDUCTION

Alveolar macrophages (AM) are recognized as archetypal 'activated' mac rophages with respect to their capacity to suppress T-cell responses t o antigen or mitogen, and this function has been ascribed an important role in the maintenance of local immunological homeostasis at the del icate blood:air interface. The present study demonstrates that this su ppression involves a unique form of T-cell anergy, in which 'AM-suppre ssed' T cells proceed normally through virtually all phases of the act ivation sequence including Ca2+ flux, T-cell receptor (TCR) modulation , cytokine [including interleukin-2 (IL-2)] secretion and IL-2 recepto r (IL-2R) expression. However, the 'suppressed' T cells fail to up-reg ulate CD2, and do not re-express normal levels of TCR-associated molec ules after initial down-modulation; moreover, they are unable to trans duce IL-2 signals leading to phosphorylation of IL-2R-associated prote ins, and remained locked in G(0)/G(1). The induction of this form of a nergy is blocked by an NO-synthase inhibitor, and is reversible upon r emoval of AM from the T cells, which then proliferate in the absence o f further stimulation. We hypothesize that this mechanism provides the means to limit the magnitude of local immune responses in this fragil e tissue microenvironment, while preserving the capacity for generatio n of immunological memory against locally encountered antigens via clo nal expansion of activated T cells after their subsequent migration to regional lymphoid organs. In an accompanying paper, we demonstrate th at a significant proportion of T cells freshly isolated from lung exhi bit a comparable surface phenotype.