International Immunology Advance Access originally published online on February 28, 2008
International Immunology 2008 20(4):601-613; doi:10.1093/intimm/dxn019
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Anti-HLA-DR-triggered monocytes mediate in vitro T cell anergy
1 Department of Medicine III, Institute for Clinical Immunology and Rheumatology, University of Erlangen-Nuremberg, Erlangen, Germany
2 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
3 Institute for Immunology, University Medical Center Schleswig-Holstein, Kiel, Germany
4 Institute of Veterinary-Biochemistry, Freie Universität Berlin, Berlin, Germany
5 Division of Hematology and Rheumatology, Department of Medicine V, University of Heidelberg, Heidelberg, Germany
Correspondence to: M. Kriegel; E-mail: mkriegel{at}bidmc.harvard.edu
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 CD3
and CTLA-4 was reduced. The hyporesponsive T cells up-regulated cell-cycle inhibitors p27kip1 and p21cip1 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.
Keywords: caspase, CD45, cell cycle, ERK, p21cip, p27kip
Received 26 April 2007, accepted 25 January 2008.