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MOG transmembrane and cytoplasmic domains contain highly stimulatory T-cell epitopes in MS.

Varrin-Doyer M, Shetty A, Spencer CM, Schulze-Topphoff U, Weber MS, Bernard CC, Forsthuber T, Cree BA, Slavin AJ, Zamvil SS - Neurol Neuroimmunol Neuroinflamm (2014)

Bottom Line: MOG p119-130, p181-195, and p186-200 elicited significantly greater T-cell responses than p35-55 in patients with MS.T cells from patients with MS proliferated significantly more strongly to MOG p119-130 and p186-200 than did T cells from HC.Recognition of these determinants is important when evaluating T-cell responses to MOG in MS and may have implications for development of myelin antigen-based therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Program in Immunology (M.V.-D., A.S., C.M.S., U.S.-T., B.A.C.C., S.S.Z.), University of California, San Francisco; Department of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia; Department of Immunology (T.F.), University of Texas at San Antonio; and Boehringer Ingelheim (A.J.S.), Ridgefield, CT.

ABSTRACT

Objective: Recently, we reported that the 218 amino acid murine full-length myelin oligodendrocyte glycoprotein (MOG) contains novel T-cell epitopes p119-132, p181-195, and p186-200, located within its transmembrane and cytoplasmic domains, and that p119-132 is its immunodominant encephalitogenic T-cell epitope in mice. Here, we investigated whether the corresponding human MOG sequences contain T-cell epitopes in patients with multiple sclerosis (MS) and healthy controls (HC).

Methods: Peripheral blood T cells from patients with MS and HC were examined for proliferation to MOG p119-130, p181-195, p186-200, and p35-55 by fluorescence-activated cell sorting analysis using carboxylfluorescein diacetate succinimidyl ester dilution assay. Intracellular production of proinflammatory cytokines was analyzed by flow cytometry.

Results: MOG p119-130, p181-195, and p186-200 elicited significantly greater T-cell responses than p35-55 in patients with MS. T cells from patients with MS proliferated significantly more strongly to MOG p119-130 and p186-200 than did T cells from HC. Further, MOG p119-130-specific T cells exhibited Th17 polarization, suggesting this T-cell epitope may be relevant to MS pathogenesis.

Conclusions: Transmembrane and cytoplasmic MOG domains contain potent T-cell epitopes in MS. Recognition of these determinants is important when evaluating T-cell responses to MOG in MS and may have implications for development of myelin antigen-based therapeutics.

No MeSH data available.


Related in: MedlinePlus

T cells from patients with multiple sclerosis (MS) exhibit a proinflammatory biasCD4+CFSElow proliferating T cells (cell division index >2) were analyzed for interleukin (IL)-17 and interferon (IFN)-γ production by intracellular staining after stimulation with phorbol 12-myristate 13-acetate/ionomycin for 5 hours. Frequencies of IL17+IFN-γ−, IL17+IFN-γ+, and IL17−IFN-γ+ were examined among proliferating p119-130–specific CD4+ T cells, p181-195–specific CD4+ T cells, and p186-200–specific CD4+ T cells. Frequencies of IL-17 and IFN-γ single positive T cells were used to calculate Th17/Th1 ratio. Box and whisker plots include the median, distribution, and range. *p < 0.05, Mann–Whitney U test. CFSE = carboxylfluorescein diacetate succinimidyl ester; HC = healthy controls.
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Figure 2: T cells from patients with multiple sclerosis (MS) exhibit a proinflammatory biasCD4+CFSElow proliferating T cells (cell division index >2) were analyzed for interleukin (IL)-17 and interferon (IFN)-γ production by intracellular staining after stimulation with phorbol 12-myristate 13-acetate/ionomycin for 5 hours. Frequencies of IL17+IFN-γ−, IL17+IFN-γ+, and IL17−IFN-γ+ were examined among proliferating p119-130–specific CD4+ T cells, p181-195–specific CD4+ T cells, and p186-200–specific CD4+ T cells. Frequencies of IL-17 and IFN-γ single positive T cells were used to calculate Th17/Th1 ratio. Box and whisker plots include the median, distribution, and range. *p < 0.05, Mann–Whitney U test. CFSE = carboxylfluorescein diacetate succinimidyl ester; HC = healthy controls.

Mentions: Th1 and Th17 cells represent 2 proinflammatory T-cell subsets that may participate in MS pathogenesis. Thus, we examined proliferating MOG peptide-specific T cells for production of proinflammatory cytokines. The frequency of Th17 cells and ratio of Th17 to Th1 cells were greater in response to MOG p119-130 than to the other MOG T-cell determinants examined (figure 2). Further, Th17 p119-130–specific T cells were statistically more frequent in patients with MS than HC. In contrast, the frequency of MOG p186-200–specific Th1 cells appeared to be higher in patients with MS than HC, but it did not reach statistical significance. Collectively, these results clearly demonstrate that the T-cell determinants within the transmembrane and cytoplasmic domains of MOG, shared in mice and humans, are highly stimulatory in patients with MS.


MOG transmembrane and cytoplasmic domains contain highly stimulatory T-cell epitopes in MS.

Varrin-Doyer M, Shetty A, Spencer CM, Schulze-Topphoff U, Weber MS, Bernard CC, Forsthuber T, Cree BA, Slavin AJ, Zamvil SS - Neurol Neuroimmunol Neuroinflamm (2014)

T cells from patients with multiple sclerosis (MS) exhibit a proinflammatory biasCD4+CFSElow proliferating T cells (cell division index >2) were analyzed for interleukin (IL)-17 and interferon (IFN)-γ production by intracellular staining after stimulation with phorbol 12-myristate 13-acetate/ionomycin for 5 hours. Frequencies of IL17+IFN-γ−, IL17+IFN-γ+, and IL17−IFN-γ+ were examined among proliferating p119-130–specific CD4+ T cells, p181-195–specific CD4+ T cells, and p186-200–specific CD4+ T cells. Frequencies of IL-17 and IFN-γ single positive T cells were used to calculate Th17/Th1 ratio. Box and whisker plots include the median, distribution, and range. *p < 0.05, Mann–Whitney U test. CFSE = carboxylfluorescein diacetate succinimidyl ester; HC = healthy controls.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4202926&req=5

Figure 2: T cells from patients with multiple sclerosis (MS) exhibit a proinflammatory biasCD4+CFSElow proliferating T cells (cell division index >2) were analyzed for interleukin (IL)-17 and interferon (IFN)-γ production by intracellular staining after stimulation with phorbol 12-myristate 13-acetate/ionomycin for 5 hours. Frequencies of IL17+IFN-γ−, IL17+IFN-γ+, and IL17−IFN-γ+ were examined among proliferating p119-130–specific CD4+ T cells, p181-195–specific CD4+ T cells, and p186-200–specific CD4+ T cells. Frequencies of IL-17 and IFN-γ single positive T cells were used to calculate Th17/Th1 ratio. Box and whisker plots include the median, distribution, and range. *p < 0.05, Mann–Whitney U test. CFSE = carboxylfluorescein diacetate succinimidyl ester; HC = healthy controls.
Mentions: Th1 and Th17 cells represent 2 proinflammatory T-cell subsets that may participate in MS pathogenesis. Thus, we examined proliferating MOG peptide-specific T cells for production of proinflammatory cytokines. The frequency of Th17 cells and ratio of Th17 to Th1 cells were greater in response to MOG p119-130 than to the other MOG T-cell determinants examined (figure 2). Further, Th17 p119-130–specific T cells were statistically more frequent in patients with MS than HC. In contrast, the frequency of MOG p186-200–specific Th1 cells appeared to be higher in patients with MS than HC, but it did not reach statistical significance. Collectively, these results clearly demonstrate that the T-cell determinants within the transmembrane and cytoplasmic domains of MOG, shared in mice and humans, are highly stimulatory in patients with MS.

Bottom Line: MOG p119-130, p181-195, and p186-200 elicited significantly greater T-cell responses than p35-55 in patients with MS.T cells from patients with MS proliferated significantly more strongly to MOG p119-130 and p186-200 than did T cells from HC.Recognition of these determinants is important when evaluating T-cell responses to MOG in MS and may have implications for development of myelin antigen-based therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Program in Immunology (M.V.-D., A.S., C.M.S., U.S.-T., B.A.C.C., S.S.Z.), University of California, San Francisco; Department of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia; Department of Immunology (T.F.), University of Texas at San Antonio; and Boehringer Ingelheim (A.J.S.), Ridgefield, CT.

ABSTRACT

Objective: Recently, we reported that the 218 amino acid murine full-length myelin oligodendrocyte glycoprotein (MOG) contains novel T-cell epitopes p119-132, p181-195, and p186-200, located within its transmembrane and cytoplasmic domains, and that p119-132 is its immunodominant encephalitogenic T-cell epitope in mice. Here, we investigated whether the corresponding human MOG sequences contain T-cell epitopes in patients with multiple sclerosis (MS) and healthy controls (HC).

Methods: Peripheral blood T cells from patients with MS and HC were examined for proliferation to MOG p119-130, p181-195, p186-200, and p35-55 by fluorescence-activated cell sorting analysis using carboxylfluorescein diacetate succinimidyl ester dilution assay. Intracellular production of proinflammatory cytokines was analyzed by flow cytometry.

Results: MOG p119-130, p181-195, and p186-200 elicited significantly greater T-cell responses than p35-55 in patients with MS. T cells from patients with MS proliferated significantly more strongly to MOG p119-130 and p186-200 than did T cells from HC. Further, MOG p119-130-specific T cells exhibited Th17 polarization, suggesting this T-cell epitope may be relevant to MS pathogenesis.

Conclusions: Transmembrane and cytoplasmic MOG domains contain potent T-cell epitopes in MS. Recognition of these determinants is important when evaluating T-cell responses to MOG in MS and may have implications for development of myelin antigen-based therapeutics.

No MeSH data available.


Related in: MedlinePlus