Anti-HLA-DR-triggered monocytes mediate in vitro T cell anergy.
Monomorphic MHC class II determinants are attractive targets for immunomodulation. HLA-DR ligation on antigen-presenting cells (APCs) can dramatically alter their function or induce cell death. In monocytes, HLA-DR triggering diminishes their capacity to stimulate T cell proliferation. To further investigate this monocyte-dependent T cell inhibition, we activated human T cells +/- HLA-DR triggering on APCs and tested whether this can induce T cell anergy. Only anti-HLA-DR, but not anti-proliferative control agent anti-CD45, could modulate monocytes in primary cultures with stimulated T cells, so that T cells were hyporesponsive during re-stimulation. Cell separation studies demonstrated that HLA-DR ligation on monocytes is sufficient for mediating T cell anergy. Secretion of monokines was severely reduced after primary culture. Monocytes anergized independently of soluble factors. Extracellular signal-regulated kinase (ERK) phosphorylation occurred early with anti-HLA-DR, but late with anti-CD45 antibody. However, ERK inhibition did not reverse the T cell-anergizing potential of HLA-DR-ligated monocytes implicating other signaling pathways involved in tolerance induction. When analyzing the anergized T cells, they were refractory to exogenous IL-2 and characterized by defective secretion of various cytokines. Expression of CD25, CD28, intracellular CD3zeta and CTLA-4 was reduced. The hyporesponsive T cells up-regulated cell-cycle inhibitors p27(kip1) and p21(cip1) in correlation with human T cell anergy. In contrast, caspase-3 and -8, known to contribute to T cell proliferation, were equally decreased in anti-HLA-DR- and anti-CD45-inhibited cultures. In summary, anti-HLA-DR treatment can generate tolerogenic monocytes transmitting T cell anergy that may be exploited for future immunomodulatory strategies to treat immune-mediated disease states.
Kriegel
Martin A
MA
Department of Medicine III, Institute for Clinical Immunology and Rheumatology, University of Erlangen-Nuremberg, Erlangen, Germany. mkriegel@bidmc.harvard.edu
Adam-Klages
Sabine
S
Gabler
Christoph
C
Blank
Norbert
N
Schiller
Martin
M
Scheidig
Christina
C
Kalden
Joachim R
JR
Lorenz
Hanns-Martin
HM
D000911:Antibodies, Monoclonal / Q000276:immunology*; D000937:Antigen-Antibody Reactions; D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000276:immunology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D006684:HLA-DR Antigens / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology*; D010766:Phosphorylation; D012016:Reference Values; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016207:Cytokines; D006684:HLA-DR Antigens; D050760:Cyclin-Dependent Kinase Inhibitor p27; D048049:Extracellular Signal-Regulated MAP Kinases