Autoreactive T cells persist in rats protected against experimental autoimmune encephalomyelitis and can be activated through stimulation of innate immunity.
Lewis rats can be rendered unresponsive to experimental autoimmune encephalomyelitis by immunization with myelin basic protein (MBP), or MBP68-86, the dominant encephalitogenic MBP epitope for this strain, administered in IFA. However, protected rats harbor potentially encephalitogenic T cells, which are maintained in an inactive state. We investigated whether these quiescent effector cells could be activated in vitro. Although these T cells respond poorly to MBP68-86, they proliferate vigorously whether cocultured with MBP68-86 and either IL-2 or IL-12, suggesting that the T cells are in a state of anergy. Moreover, we could activate these anergic T cells with peptide and cytosine-guanine dinucleotide (CpG) oligonucleotide, but not control oligonucleotide, suggesting that products of the innate immune response are capable of activating anergic autoreactive T cells. The activated T cells produced the proinflammatory cytokine, IFN-gamma in response to IL-12, and IL-6 was secreted in response to CpG oligonucleotide. IL-6 has been reported to play a role in T cell activation by blocking T regulatory/suppressor (Treg) cell-mediated suppression through a Toll-like receptor-dependent pathway. However, anti-IL-6 mAb did not block CpG activation of the anergized cells. In contrast, anti-TGF-beta(1) Ab released the unresponsive T cells from the anergic state in the presence of MBP68-86, whereas TGF-beta(1) inhibited proliferation of MBP68-86- plus CpG-activated T cells. Because TGF-beta(1) has previously been implicated in Treg activity, this finding is consistent with a role for Treg cells in maintaining autoreactive T cells in the anergic state.
Conant
Stephanie B
SB
Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Swanborg
Robert H
RH
D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D005620:Freund's Adjuvant / Q000008:administration & dosage / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D008055:Lipids / Q000008:administration & dosage / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000008:administration & dosage / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D053773:Transforming Growth Factor beta1
C408982:CPG-oligonucleotide; D008055:Lipids; D004676:Myelin Basic Protein; D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C114843:incomplete Freund's adjuvant; C110235:myelin basic protein 68-86; D018664:Interleukin-12; D007371:Interferon-gamma; D005620:Freund's Adjuvant