MACROPHAGE MEDIATED IMMUNOREGULATION VIA TRYPTOPHAN

Project: Research project

Project Details

Description

DESCRIPTION: (Adapted from the applicant's abstract)
Macrophages phagocytose microorganisms and present antigens to T cells.
Paradoxically, however, macrophages are also professional scavengers
which normally phagocytose and present antigens derive from self
proteins. The long-term goal of this project is to identify the
mechanism by which macrophages inhibit autoimmune responses to these
self antigens. The applications have identified a novel mechanism
whereby macrophages may present antigens in an immunosuppressive, rather
than immunostimulatory fashion. They show that macrophages that have
differentiated under the influence of macrophage colony-stimulating
factor (MCSF) inhibit attempted T cell activation. The mechanism of this
inhibition is massive induction of the enzyme indoleamine 2, 3-
dioxygenase (IDO), which selectively degrades the essential amino acid
tryptophan. Simultaneously, MCSF-derived macrophages markedly increase
trypthphan uptake via induction of a novel high-affinity, tryptophan-
selective transport pathway. The applicants hypothesize that the
combination of these two mechanisms allows macrophages to rapidly
deplete tryptophan from the local microenvironment, thus aborting normal
T cell activation. Consistent with the proposed role of IDO in
suppresssing T cells, the applicants show that pharmacologic inhibition
of IDO in vivo results in enhanced activation of autoreactive T cells,
and that inhibition of IDO activity in placenta results in rapid,
uniform, T cell-mediated rejection of all allogeneic fetuses. The aims
of the current proposal are to: (1) test the hypothesis that a
synergistic combination of IFNgamma and CD40-ligand expression by T
cells triggers IDO expression in macrophages, and characterize the
effect of the resulting tryptophan depletion on T cell activation; (2)
use a transgenic mouse model to test the hypothesis that IDO-expressing
macrophages inhibit autoreactive T cell activation in vivo; and (3)
define the functional characteristics and regulation of the high-
affinity tryptophan transport system. These studies will define a
fundamental and previously unsuspected mechanism of T cell regulation
imposed by cells of the innate immune system.
StatusFinished
Effective start/end date1/1/9912/31/03

ASJC

  • Medicine(all)