Characterization of Myelin Oligodendrocyte Glycoprotein (MOG)35–55-Specific CD8+ T Cells in Experimental Autoimmune Encephalomyelitis
Multiple sclerosis (MS) is a chronic autoimmune disease that primarily affects the central nervous system (CNS). The pathogenesis of MS is largely mediated by T cells, which are activated by CNS autoantigens and subsequently damage the myelin sheath, leading to the formation of active lesions in the CNS. While most studies have focused on the role of CD4+ T cells in MS and its animal model, experimental autoimmune encephalomyelitis (EAE), there is increasing evidence that CD8+ T cells also play a significant role in the disease process. This study aims to characterize the pathological interrelationship between CD4+ and CD8+ autoreactive T cells in MS/EAE, with a particular focus on myelin oligodendrocyte glycoprotein (MOG)35–55-specific CD8+ T cells.
The study utilized female C57BL/6 mice, which were immunized with MOG35–55 peptide to induce EAE. Fourteen days post-immunization, T cells were isolated from the spleen and purified into CD4+ and CD8+ subsets using isolation kits. The purity of these cells was confirmed by flow cytometric analysis, which showed that CD8+CD3+ and CD4+CD3+ cells were 86% and 94% pure, respectively. These purified T cells were then stimulated with MOG35–55 peptide and subjected to proliferation assays. The results indicated that while CD8+ T cells generally had a lower response to MOG35–55 compared to CD4+ T cells, their response was not entirely dependent on CD4+ T cells. Specifically, at the highest dose of MOG35–55 peptide (20 µg/mL), CD8+ T cells exhibited a proliferative response of 21,526 ± 1,236 counts per minute (cpm), compared to 63,953 ± 3,284 cpm for CD4+ T cells.
Cytokine profiles of the activated T cells were also examined. Enzyme-linked immunosorbent assays (ELISAs) revealed that CD8+ T cells secreted lower levels of interferon-gamma (IFN-γ) and interleukin-4 (IL-4) compared to CD4+ T cells. At the highest dose of MOG35–55 peptide, CD8+ T cell supernatants contained 803.3 ± 39.2 pg/mL of IFN-γ and 245.5 ± 11.8 pg/mL of IL-4, whereas CD4+ T cell supernatants contained 1,451.3 ± 59.4 pg/mL of IFN-γ and 298.6 ± 7.7 pg/mL of IL-4.
To further investigate the role of MOG35–55-specific CD8+ T cells in EAE pathogenesis, an adoptive transfer experiment was conducted. Naive B6 mice were injected with either MOG35–55-specific CD8+ or CD4+ T cells from immunized B6 mice. The clinical course of EAE was monitored using a 0–5 scale, and spinal cord tissues were examined histologically. The results showed that both CD8+ and CD4+ T cells were capable of inducing EAE, with similar clinical scores observed in both groups. Histological examination revealed slight inflammation and demyelination in the spinal cords of mice that received CD8+ T cells, consistent with previous observations. Interestingly, the pathology in mice transferred with CD8+ T cells was slightly worse compared to those transferred with CD4+ T cells.
The findings of this study suggest that while CD8+ autoreactive T cells in EAE have a lower encephalitogenic function compared to their CD4+ counterparts, they are nonetheless capable of independently inducing EAE. This indicates that CD8+ T cells play a unique and significant role in the pathogenesis of MS/EAE, which has been largely overlooked in previous research. The study also highlights the importance of considering both CD4+ and CD8+ T cells in the development of therapeutic strategies for MS.
The data presented in this study are consistent with previous findings in other autoimmune models, such as experimental autoimmune uveitis (EAU) and type I diabetes, where CD8+ autoreactive T cells have been shown to play a critical role. The similarities in the functional profiles of CD4+ and CD8+ autoreactive T cells across different autoimmune diseases suggest a common underlying mechanism, possibly involving the release of autoreactive T cells from the thymus and their subsequent activation by local autoantigens in the periphery.
Future research directions could include a comparative analysis of CD8+ autoreactive T cells in different autoimmune models, such as EAE, EAU, and type I diabetes, to further elucidate their role in autoimmune pathogenesis. Additionally, investigating the influence of different dendritic cell (DC) subsets on the differentiation of MOG35–55-specific T cells could provide valuable insights into the mechanisms underlying T cell activation and differentiation in autoimmune diseases.
In conclusion, this study provides important insights into the role of MOG35–55-specific CD8+ T cells in the pathogenesis of EAE. The findings underscore the need for a more comprehensive understanding of the contributions of both CD4+ and CD8+ T cells in MS/EAE, which could lead to the development of more effective therapeutic strategies for these debilitating diseases.
doi.org/10.1097/CM9.0000000000000551
Was this helpful?
0 / 0