T Cell Repertoire Diversity Is Required for Relapses in Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis

Abstract

Comparison of TCRαβ repertoires of myelin oligodendrocyte glycoprotein (MOG)-specific T lymphocytes in C57BL/6 and TdT-deficient littermates (TdT−/−) generated during experimental autoimmune encephalomyelitis (EAE) highlights a link between a diversified TCRαβ repertoire and EAE relapses. At the onset of the disease, the EAE-severity is identical in TdT+/− and TdT−/− mice and the neuropathologic public MOG-specific T cell repertoires express closely similar public Vα-Jα and Vβ-Jβ rearrangements in both strains. However, whereas TdT+/+ and TdT+/− mice undergo successive EAE relapses, TdT−/− mice recover definitively and the lack of relapses does not stem from dominant regulatory mechanisms. During the first relapse of the disease in TdT+/− mice, new public Vα-Jα and Vβ-Jβ rearrangements emerge that are distinct from those detected at the onset of the disease. Most of these rearrangements contain N additions and are found in CNS-infiltrating T lymphocytes. Furthermore, CD4+ T splenocytes bearing these rearrangements proliferate to the immunodominant epitope of MOG and not to other immunodominant epitopes of proteolipid protein and myelin basic protein autoantigens, excluding epitope spreading to these myelin proteins. Thus, in addition to epitope spreading, a novel mechanism involving TCRαβ repertoire diversification contributes to autoimmune progression.

Hippocampal T cell infiltration promotes neuroinflammation and cognitive decline in a mouse model of tauopathy

“…Preparation of CNS-immune cells was performed using Percoll® separation as described previously (Fazilleau et al , 2007). Briefly, mice were perfused with phosphate-buffered saline (PBS) and the brains were dissected out and homogenized in 5 ml of PBS with collagenase IV at 0.2 mg/ml and DNase I at 1 mg/ml (both from Sigma-Aldrich) for 30 min at 37°C and 5% CO 2 .…”

Bispecificity for Myelin and Neuronal Self-Antigens Is a Common Feature of CD4 T Cells in C57BL/6 Mice

“…In our panel of 22 T cell hybridomas, we could identify 7 bispecific TCR that are different from each other and from the 2D2 TCR in term of Va-Ja and Vb-Jb gene usage. One Va4-Ja31 (TRAV6D-TRAJ31) rearrangement was fully shared by two MOG-monospecific TCR (1MOG35 and 1MOG231), resulting in a DNSNNRI CDR3a sequence resembling the public RNSNNRI sequence detected in MOG-reactive T cell lines and CNSinfiltrating T cells (60,61). The 1MOG35 and 1MOG231 TCR also used the same Jb gene segment but with different Vb, resulting in different CDR3b lengths and sequences.…”

“…Interestingly, whereas the N is germlineencoded, the G results from junctional diversity, suggesting a nonrandom association between this CDR3 residue and the bispecificity for MOG and NF-M . Of note, the Ja23 gene segment is used in public rearrangements with the Va9 segment, translating into NYNQGKL, SYNQGKL, or GYNQGKL CDRa motifs identical to the ones reported in this study (60,61).…”

Accelerated Course of Experimental Autoimmune Encephalomyelitis in PD-1-Deficient Central Nervous System Myelin Mutants

“…35 We therefore tested animals at the peak of disease for reactivity against a number of MHC class II-related myelin peptides (MOG 113-127 , MOG 120-134 , MOG [183][184][185][186][187][188][189][190][191][192][193][194][195][196][197] , MBP 54-72 , PLP [178][179][180][181][182][183][184][185][186][187][188][189][190][191] ). 36 However, no relevant MHC class II restricted responses against other myelin peptides than MOG were detectable (data not shown). Because the pathogenic inflammatory response in PLPtg mice is mediated by CD8 ϩ T cells 11,12 we also tested for responses after antigenic stimulation with a number of MHC class I myelin peptides mentioned in the Materials and Methods.…”