Thymic selection depends on positive and negative selective mechanisms based on the avidity of T cell interaction with antigen–major histocompatibility complex complexes. However, peripheral mechanisms for the recruitment and clonal expansion of the responding T cell repertoire remain obscure. Here we provide evidence for an avidity-based model of peripheral T cell clonal expansion in response to antigenic challenge. We have used the encephalitogenic, H-2 Au-restricted, acetylated NH2-terminal nonameric peptide (Ac1-9) epitope from myelin basic protein as our model antigen. Peptide analogues were generated that varied in antigenic strength (as assessed by in vitro assay) based on differences in their binding affinity for Au. In vivo, these analogues elicited distinct repertoires of T cells that displayed marked differences in antigen sensitivity. Immunization with the weakest (wild-type) antigen expanded the high affinity T cells required to induce encephalomyelitis. In contrast, immunization with strongly antigenic analogues led to the elimination of T cells bearing high affinity T cell receptors by apoptosis, thereby preventing disease development. Moreover, the T cell repertoire was consistently tuned to respond to the immunizing antigen with the same activation threshold. This tuning mechanism provides a peripheral control against the expansion of autoreactive T cells and has implications for immunotherapy and vaccine design.
The rules governing which T cells are inactivated during peptide-induced tolerance are unclear. Here we show that MBP(89-101) contains three overlapping but distinct T cell epitopes that are restricted by a single major histocompatibility complex (MHC) class II molecule. The dominant epitope is not processed from MBP and is not relevant to the induction of autoimmunity. Pathogenic T cells recognize two minor epitopes that are processed from MBP but are presented only poorly after exposure to MBP(89-101). Induction of immunological tolerance by MBP(89-101) therefore inactivates T cells that recognize the dominant epitope and disease-relevant T cells escape tolerance. The topology of the three epitopes implicates asparagine endopeptidase as the enzyme that controls recognition of this region of MBP. Our results highlight the need to use peptides that mimic the binding of processed antigen fragments to MHC molecules for successful modulation of disease-relevant T cells.
The neuropeptide galanin is widely expressed by many differing subsets of neurons in the nervous system. There is a marked upregulation in the levels of the peptide in a variety of nerve injury models and in the basal forebrain of humans with Alzheimer's disease. Here we demonstrate that galanin expression is specifically and markedly upregulated in microglia both in multiple sclerosis (MS) lesions and shadow plaques. Galanin expression is also upregulated in the experimental autoimmune encephalomyelitis (EAE) model of MS, although solely in oligodendrocytes. To study whether the observed increase in expression of galanin in inflammatory demyelination might modulate disease activity, we applied the EAE model to a panel of galanin transgenic lines. Over-expression of galanin in transgenic mice (Gal-OE) abolishes disease in the EAE model, whilst loss-of-function mutations in galanin or galanin receptor-2 (GalR2) increase disease severity. The pronounced effects of altered endogenous galanin or GalR2 expression on EAE disease activity may reflect a direct neuroprotective effect of the neuropeptide via activation of GalR2, similar to that previously described in a number of neuronal injury paradigms. Irrespective of the mechanism(s) by which galanin alters EAE disease activity, our findings imply that galanin/GalR2 agonists may have future therapeutic implications for MS.EAE ͉ GalR2 ͉ Glia ͉ multiple sclerosis T he neuropeptide galanin (1) is widely, but by no means ubiquitously, expressed in the adult brain (2-5), and following injury there is a dramatic increase in the levels of the peptide in many neuronal subpopulations (6-8) and in the basal forebrain of patients with Alzheimer's disease (9, 10). In addition to the neuronal expression of galanin, a small number of reports have shown that the neuropeptide is also expressed by oligodendrocyte or microglial cells following cortical spreading depression (11), transient forebrain ischaemia (12) or colchicine treatment (13,14). Of note, the adult Gal-OE mice used in this study have a marked increase in neuronal galanin expression that is predominantly in the terminal fields of the hippocampus (15). Before the current study there was no evidence that galanin was expressed in non-neuronal cells in these mice.We have previously shown that kainic acid-induced cell death in the CA1 and CA3 regions of the hippocampus is markedly reduced in Gal-OE mice compared to WT controls (15). Similarly, in vitro treatment with staurosporine or glutamate induced significantly less cell death in hippocampal cultures from Gal-OE animals than in WT controls (15). In contrast, Gal-KO mice demonstrated more hippocampal cell death following in vivo and in vitro neuronal damage than WT controls (15). Furthermore the addition of exogenous galanin peptide or the GalR2/3-specific agonist Gal2-11 reduced the amount of cell death when co-administered with either glutamate or staurosporine in WT primary hippocampal cultures (15). We have recently extended these findings by demonstrating that organo...
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