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1.
J Immunol ; 206(6): 1151-1160, 2021 03 15.
Article in English | MEDLINE | ID: mdl-33558376

ABSTRACT

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the CNS. We have previously demonstrated that CNS-specific CD8 T cells possess a disease-suppressive function in MS and variations of its animal model, experimental autoimmune encephalomyelitis (EAE), including the highly clinically relevant relapsing-remitting EAE disease course. Regulatory CD8 T cell subsets have been identified in EAE and other autoimmune diseases, but studies vary in defining phenotypic properties of these cells. In relapsing-remitting EAE, PLP178-191 CD8 T cells suppress disease, whereas PLP139-151 CD8 T cells lack this function. In this study, we used this model to delineate the unique phenotypic properties of CNS-specific regulatory PLP178-191 CD8 T cells versus nonregulatory PLP139-151 or OVA323-339 CD8 T cells. Using multiparametric flow cytometric analyses of phenotypic marker expression, we identified a CXCR3+ subpopulation among activated regulatory CD8 T cells, relative to nonregulatory counterparts. This subset exhibited increased degranulation and IFN-γ and IL-10 coproduction. A similar subset was also identified in C57BL/6 mice within autoregulatory PLP178-191 CD8 T cells but not within nonregulatory OVA323-339 CD8 T cells. This disease-suppressing CD8 T cell subpopulation provides better insights into functional regulatory mechanisms, and targeted enhancement of this subset could represent a novel immunotherapeutic approach for MS.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Multiple Sclerosis/immunology , Myelin Sheath/pathology , T-Lymphocyte Subsets/immunology , Adoptive Transfer , Animals , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/transplantation , Cell Separation , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Flow Cytometry , Humans , Interferon-gamma/metabolism , Interleukin-10/metabolism , Mice , Multiple Sclerosis/pathology , Myelin Sheath/immunology , Receptors, CXCR3/metabolism , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/transplantation
2.
Front Immunol ; 11: 568630, 2020.
Article in English | MEDLINE | ID: mdl-33193343

ABSTRACT

Autoimmune diseases are characterized by regulatory deficit in both the CD4+ and CD8+ T-cell compartments. We have shown that CD8+ T-cells associated with acute relapse of multiple sclerosis are significantly deficient in their immune suppressive ability. We hypothesized that distinct CD8+ cytotoxic T-cell (Tc) lineages, determined by cytokine milieu during naïve T-cell differentiation, may harbor differential ability to suppress effector CD4+ T-cells. We differentiated purified human naïve CD8+ T-cells in vitro toward Tc0 (media control), Tc1 and Tc17 lineages. Using in vitro flow cytometric suppression assays, we observed that Tc0 and Tc17 cells had similar suppressive ability. In contrast, Tc1 cells showed significant loss of suppressive ability against ex vivo CD4+ T-cells and in vitro-differentiated Th0, Th1 and Th17 cells. Of note, Tc1 cells were also suboptimal in suppressing CD4-induced acute xenogeneic graft versus host disease (xGVHD) in vivo. Tc subtypes derived under various cytokine combinations revealed that IL-12-containing conditions resulted in less suppressive cells exhibiting dysregulated cytotoxic degranulation. RNA sequencing transcriptome analyses indicated differential regulation of inflammatory genes and enrichment in GM-CSF-associated pathways. These studies provide insights into the role of T-cell differentiation in CD8 suppressive biology and may reveal therapeutically targetable pathways to reverse suppressive deficit during immune-mediated disease.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Interleukin-12/immunology , Animals , CD4-Positive T-Lymphocytes/immunology , Cell Differentiation , Female , Graft vs Host Disease/immunology , Humans , Immune Tolerance , Mice
3.
J Immunol ; 205(2): 359-368, 2020 07 15.
Article in English | MEDLINE | ID: mdl-32532836

ABSTRACT

Investigating the complex cellular interplay controlling immunopathogenic and immunoregulatory responses is critical for understanding multiple sclerosis (MS) and for developing successful immunotherapies. Our group has demonstrated that CNS myelin-specific CD8 T cells unexpectedly harbor immune regulatory capacity in both mouse and human. In particular, PLP178-191-specific CD8 T cells (PLP-CD8) robustly suppress the MS mouse model experimental autoimmune encephalomyelitis. We have recently shown that this depends on PLP-CD8 elaborating IFN-γ and perforin in a coordinated suppression program over time. However, the cellular target and downstream effects of CD8 T cell-derived IFN-γ remains poorly understood. In this study, we show that although wild-type (WT) PLP-CD8 were robustly suppressive in IFN-γR-deficient mice, IFN-γR-deficient PLP-CD8 exhibited suboptimal suppression in WT mice. Compared with WT counterparts, IFN-γR-deficient PLP-CD8 were defective in suppressing disease in IFN-γ-deficient recipients, a scenario in which the only IFN-γ available to WT PLP-CD8 is that which they produce themselves. Further, we found that IFN-γR-deficient PLP-CD8 exhibited altered granzyme/IFN-γ profiles, altered migration in recipients, and deficits in killing capacity in vivo. Collectively, this work suggests that IFN-γ responsiveness allows myelin-specific CD8 T cells to optimally perform autoregulatory function in vivo. These insights may help elucidate future adoptive immunotherapeutic approaches for MS patients.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Central Nervous System/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Interferon-gamma/metabolism , Multiple Sclerosis/immunology , Animals , Autoantigens/immunology , Autoimmunity , Cells, Cultured , Disease Models, Animal , Female , Humans , Immune Tolerance , Interferon-gamma/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Myelin Proteolipid Protein/immunology , Myelin Sheath/immunology , Peptide Fragments/immunology , Receptors, Interferon/genetics , Receptors, Interferon/metabolism , Interferon gamma Receptor
4.
Sci Rep ; 10(1): 5011, 2020 03 19.
Article in English | MEDLINE | ID: mdl-32193439

ABSTRACT

Therapeutic success of B cell-targeting approaches in multiple sclerosis (MS) has intensified research into the pathogenic and regulatory roles these cells play in demyelinating disease. Dissecting the function of B cells in the MS mouse model experimental autoimmune encephalomyelitis (EAE) is largely confined to induction with either the myelin oligodendrocyte glycoprotein epitope MOG35-55 or the full-length recombinant human MOG protein, the latter representing the most-used B cell-dependent EAE model. There is a clear need to investigate B cell function in additional myelin antigen contexts. Unlike MOG35-55, where lack of B cells yields more severe disease, we show here that the immunodominant myelin proteolipid protein epitope (PLP178-191) elicited identical EAE in WT and µMT mice, suggesting an absence of B cell engagement by this peptide. We hypothesized that a longer PLP antigen may better engage B cells and designed a peptide encompassing the extracellular domains (ECD) of PLP. We demonstrate here that PLPECD-immunized B cell-deficient mice failed to exhibit EAE. In contrast, PLPECD induced EAE not only in WT mice, but in B cell-sufficient mice incapable of secreting antibodies, suggesting a predominant antigen presentation role. These results establish a novel, efficient B cell-dependent EAE model.


Subject(s)
B-Lymphocytes/immunology , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental , Multiple Sclerosis , Myelin-Oligodendrocyte Glycoprotein , Animals , Encephalomyelitis, Autoimmune, Experimental/immunology , Epitopes , Mice, Inbred C57BL , Multiple Sclerosis/etiology , Multiple Sclerosis/immunology , Myelin Proteolipid Protein/immunology , Peptide Fragments/immunology , Protein Domains
5.
Article in English | MEDLINE | ID: mdl-32161909

ABSTRACT

Multiple Sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). We have shown that CNS-specific CD8 T cells (CNS-CD8) possess a disease suppressive function in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Previous studies have focused on the role of these cells predominantly in chronic models of disease, but the majority of MS patients present with a relapsing-remitting disease course. In this study, we evaluated the therapeutic role of CD8 T cells in the context of relapsing-remitting disease (RR-EAE), using SJL mice. We found that PLP178-191- and MBP84-104-CD8 ameliorated disease severity in an antigen-specific manner. In contrast, PLP139-151-CD8 did not suppress disease. PLP178-191-CD8 were able to reduce the number of relapses even when transferred during ongoing disease. We further ascertained that the suppressive subset of CD8 T cells was contained within the CD25+ CD8 T cell compartment post-in vitro activation with PLP178-191. Using Listeria monocytogenes (LM) encoding CNS antigens to preferentially prime suppressive CDS T cells in vivo, we show that LM infection induced disease suppressive CD8 T cells that protected and treated PLP178-191 disease. Importantly, a combination of PLP178-191-CDs transfer boosted by LM-PLP175-194 infection effectively treated ongoing disease induced by a non-cognate peptide (PLP139-151), indicating that this approach could be effective even in the context of epitope spreading. These data support a potential immunotherapeutic strategy using CD8 transfer and/or LM vaccination to boost disease regulatory CD8 T cells.

6.
Front Immunol ; 9: 2336, 2018.
Article in English | MEDLINE | ID: mdl-30356717

ABSTRACT

Pathogenesis of immune-mediated demyelinating diseases like multiple sclerosis (MS) is thought to be governed by a complex cellular interplay between immunopathogenic and immunoregulatory responses. We have previously shown that central nervous system (CNS)-specific CD8 T cells have an unexpected protective role in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). In this study, we interrogated the suppressive potential of PLP178-191-specific CD8 T cells (PLP-CD8). Here, we show that PLP-CD8, when administered post-disease onset, rapidly ameliorated EAE progression, and suppressed PLP178-191-specific CD4 T cell responses as measured by delayed-type hypersensitivity (DTH). To accomplish DTH suppression, PLP-CD8 required differential production of perforin and IFNγ. Perforin was not required for the rapid suppressive action of these cells, but was critical for maintenance of optimal longer term DTH suppression. Conversely, IFNγ production by PLP-CD8 was necessary for swift DTH suppression, but was less significant for maintenance of longer term suppression. These data indicate that CNS-specific CD8 T cells employ an ordered regulatory mechanism program over a number of days in vivo during demyelinating disease and have mechanistic implications for this immunotherapeutic approach.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Demyelinating Autoimmune Diseases, CNS/etiology , Demyelinating Autoimmune Diseases, CNS/metabolism , Interferon-gamma/metabolism , Perforin/metabolism , Animals , Autoimmunity , Cytotoxicity, Immunologic , Disease Models, Animal , Disease Progression , Encephalomyelitis, Autoimmune, Experimental , Immunomodulation , Interferon-gamma/genetics , Mice , Mice, Knockout , Multiple Sclerosis , Perforin/genetics , T-Cell Antigen Receptor Specificity
7.
Sci Rep ; 7(1): 1519, 2017 05 08.
Article in English | MEDLINE | ID: mdl-28484224

ABSTRACT

CD8 T-cells predominate in CNS lesions of MS patients and display oligoclonal expansion. However, the role of myelin-specific CD8 T-cells in disease remains unclear, with studies showing protective and pathogenic roles in EAE. We demonstrated a disease-suppressive function for CNS-specific CD8 T-cells in a model where the antigen is exogenously administered in vivo and used for in vitro activation. To probe the nature of the CD8 response elicited by endogenously presented myelin antigens in vivo, we developed a novel approach utilizing infection with Listeria monocytogenes (LM) encoding proteolipid protein peptide (PLP) amino acids 178-191 (LM-PLP). LM-PLP infection preferentially induced PLP-specific CD8 T-cell responses. Despite the induction of PLP-specific CD8 T-cells, LM-PLP infection did not result in disease. In fact, LM-PLP infection resulted in significant amelioration of PLP178-191-induced EAE. Disease suppression was not observed in mice deficient in CD8 T-cells, IFN-γ or perforin. DTH responses and CNS infiltration were reduced in protected mice, and their CD4 T-cells had reduced capacity to induce tissue inflammation. Importantly, infection with LM-PLP ameliorated established disease. Our studies indicate that CD8 T-cells induced by endogenous presentation of PLP178-191 attenuate CNS autoimmunity in models of EAE, implicating the potential of this approach as a novel immunotherapeutic strategy.


Subject(s)
Antigens, Bacterial/metabolism , CD8-Positive T-Lymphocytes/immunology , Central Nervous System/pathology , Encephalomyelitis, Autoimmune, Experimental/immunology , Listeria/metabolism , Lymphocyte Activation/immunology , Animals , Encephalomyelitis, Autoimmune, Experimental/pathology , Immunity, Cellular , Mice, Inbred C57BL , Mice, Knockout , Myelin Proteolipid Protein/immunology , Organ Specificity
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