Prevention and treatment of experimental autoimmune encephalomyelitis with clonotypic CDR3 peptides: CD4(+) Foxp3(+) T-regulatory cells suppress interleukin-2-dependent expansion of myelin basic protein-specific T cells.
T-cell receptor (TCR)-derived peptides are recognized by the immune system and are capable of modulating autoimmune responses. Using the myelin basic protein (MBP) TCR 1501 transgenic mouse model, we demonstrated that TCR CDR3 peptides from the transgenic TCR can provide a protective effect when therapy is initiated before the induction of experimental autoimmune encephalomyelitis (EAE). More importantly, TCR CDR3 peptide therapy can ameliorate the disease when administered after EAE onset. Concurrent with the therapeutic effects, we observed reduced T-cell proliferation and reduced interleukin-2 (IL-2) levels in response to stimulation with MBP-85-99 peptide in splenocyte cultures from mice receiving TCR CDR3 peptides compared with that of control mice. Moreover, we found that Foxp3(+) CD4 T cells from mice protected with TCR CDR3 peptide are preferentially expanded in the presence of IL-2. This is supportive of a proposed mechanism where Foxp3(+) T-regulatory cells induced by therapy with MBP-85-99 TCR CDR3 peptides limit expansion and the encephalitogenic activity of MBP-85-99-specific T cells by regulating the levels of secreted IL-2.
Buenafe
Abigail C
AC
Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA. buenafea@ohsu.edu
Andrew
Shayne
S
Afentoulis
Michael
M
Offner
Halina
H
Vandenbark
Arthur A
AA
D000818:Animals; D002469:Cell Separation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000627:therapeutic use*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D010455:Peptides / Q000627:therapeutic use; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta; C107908:myelin basic protein 85-99