Feedback Regulation of Murine Autoimmunity via Dominant Anti-Inflammatory Effects of Interferon γ

Minguela, Alfredo; Pastor, Silvia; Mi, Wentao; Richardson, James A.; Ward, E. Sally

doi:10.4049/jimmunol.178.1.134

Cited by 25 publications

(37 citation statements)

References 74 publications

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“…Therefore, to avoid immunologic exhaustion and to focus on the competitive activities among T cell clones, an eightfold lower amount of 25 μg was used for all subsequent APL immunizations. These results correspond with the findings that Ac1-9(Y4) induces severe EAE at low but not high concentrations (15).…”

Section: Resultssupporting

confidence: 79%

Molecular mimics can induce a nonautoaggressive repertoire that preempts induction of autoimmunity

Maverakis

Menezes

Ametani

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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To determine the role that competition plays in a molecular mimic's capacity to induce autoimmunity, we studied the ability of naïve encephalitogenic T cells to expand in response to agonist altered peptide ligands (APLs), some capable of stimulating both self-directed and exclusively APL-specific T cells. Our results show that although the APLs capable of stimulating exclusively APLspecific T cells are able to expand encephalitogenic T cells in vitro, the encephalitogenic repertoire is effectively outcompeted in vivo when the APL is used as the priming immunogen. Competition as a mechanism was supported by: (i) the demonstration of a population of exclusively APL-specific T cells, (ii) an experiment in which an encephalitogenic T cell population was successfully outcompeted by adoptively transferred naïve T cells, and (iii) demonstrating that the elimination of competing T cells bestowed an APL with the ability to expand naïve encephalitogenic T cells in vivo. In total, these experiments support the existence of a reasonably broad T cell repertoire responsive to a molecular mimic (e.g., a microbial agent), of which the exclusively mimic-specific component tends to focus the immune response on the invading pathogen, whereas the rare cross-reactive, potentially autoreactive T cells are often preempted from becoming involved.experimental autoimmune encephalomyelitis | molecular mimicry | multiple sclerosis | driver clones | autoimmune T cell recognition is degenerate; a single T cell can react to a heterogeneous assortment of ligands (1-5). The use of synthetic combinatorial peptide libraries has revealed two key features of this degeneracy: (i) There are a vast number of agonistic ligands for a single clone (possibly >10 6 ) each falling along a spectrum of stimulatory potencies and (ii) the native self determinant is often "suboptimal" when compared with many of the synthetic mimic peptides (4). The concept of molecular mimicry describes a situation in which a foreign microbe can initiate an immune response in which a T or B cell component cross-recognizes self. The amino acid sequence in the mimic determinant and the native self-determinant can be very different and in some instances, apparently chemically unrelated. Although several groups have demonstrated degenerate recognition by autoreactive T cells (1, 6, 7), molecular mimicry as a direct cause of autoimmunity has only rarely been shown (6).We have used the term "driver" to refer to individual selfdirected T cell clones that are required to propagate an autoimmune response. In this paper we ask whether APL-specific, nonself-directed T cells can outcompete naïve driver pathogenic clones for activation. The APLs used in our study can be considered analogous to microbial molecular mimics. The ability of these APLs to induce non-self-directed exclusively APL-specific clones was studied in the myelin basic protein (MBP):Ac1-9-induced B10.PL (H-2 u ) model of experimental autoimmune encephalomyelitis (EAE). EAE is an autoimmune demyelinating disease of the cent...

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Section: Resultssupporting

confidence: 79%

Molecular mimics can induce a nonautoaggressive repertoire that preempts induction of autoimmunity

Maverakis

Menezes

Ametani

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus, while low levels of IFN-␥ in DR3 mice are proinflammatory, high levels in DR3DQ6 mice are protective. Although IFN-␥ is considered a proinflammatory cytokine, the anti-inflammatory role of IFN-␥ is well-established (31)(32)(33)(34)(35)(36)(37). Genetic deletion of IFN-␥ or IFN-R gene caused exacerbation of EAE in a certain strain of mice (35,37,38).…”

Section: Discussionmentioning

confidence: 99%

HLA-DQ6 (DQB1*0601)-Restricted T Cells Protect against Experimental Autoimmune Encephalomyelitis in HLA-DR3.DQ6 Double-Transgenic Mice by Generating Anti-Inflammatory IFN-γ

Mangalam¹,

Luckey²,

Basal³

et al. 2008

The Journal of Immunology

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The human MHC class II genes are associated with genetic susceptibility to multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the CNS of presumed autoimmune origin. These genes encode for proteins responsible for shaping immune response. The exact role of HLA-DQ and -DR genes in disease pathogenesis is not well-understood due to the high polymorphism, linkage disequilibrium, and heterogeneity of human populations. The advent of HLA class II-transgenic (Tg) mice has helped in answering some of these questions. Previously, using single-Tg mice (expressing the HLA-DR or -DQ gene), we showed that proteolipid protein (PLP)91–110 peptide induced classical experimental autoimmune encephalomyelitis only in DR3.Aβ° mice, suggesting that DR3 (DRB1*0301) is a disease susceptible gene in the context of PLP. Human population studies have suggested that HLA-DQ6 (DQB1*0601) may be a protective gene in MS. To test this disease protection in an experimental model, we generated double-Tg mice expressing both HLA-DR3 and -DQ6. Introduction of DQ6 onto DR3-Tg mice led to a decrease in disease incidence on immunization with PLP91–110 peptide indicating a dominant protective role of DQ6. This protective effect is due to high levels of IFN-γ produced by DQ6-restricted T cells, which suppressed proliferation of encephalitogenic DR3-restricted T cells by inducing apoptosis. Our study indicates that DQ6 modifies the PLP91–110-specific T cell response in DR3 through anti-inflammatory effects of IFN-γ, which is protective for experimental autoimmune encephalomyelitis. Thus, our double-Tg mouse provides a novel model in which to study epistatic interactions between HLA class II molecules in MS.

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“…The importance of the preservation of IFN-␥ production by 45D is highlighted by numerous studies revealing a protective, anti-inflammatory role of IFN-␥ in EAE (12)(13)(14)(15)(16)(17)(18)(19)(20). Moreover, it has been reported that the poor encephalitogenicity of a high-affinity myelin-associated MHC variant peptide can be reversed by anti-IFN-␥ Ab (30). Given the protective role of IFN-␥ in EAE and the ability of 45D to maintain IFN-␥ production by MOG-reactive CD4 ϩ T cells, we hypothesized that IFN-␥ was required to inhibit the responsiveness of myelin-reactive CD4 ϩ T cells to weak MHC variant peptides and thereby prevented the induction of EAE.…”

Section: Discussionmentioning

confidence: 99%

Loss of IFN-γ Enables the Expansion of Autoreactive CD4+ T Cells to Induce Experimental Autoimmune Encephalomyelitis by a Nonencephalitogenic Myelin Variant Antigen

Sabatino

Shires

Altman

et al. 2008

The Journal of Immunology

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MHC variant peptides are analogues of immunogenic peptides involving alterations of the MHC-binding residues, thereby altering the affinity of the peptide for the MHC molecule. Recently, our laboratory demonstrated that immunization of WT B6 mice with 45D, a low-affinity MHC variant peptide of MOG35–55, results in significantly attenuated experimental autoimmune encephalomyelitis (EAE), yet IFN-γ production is comparable to myelin oligodendrocyte glycoprotein (MOG)35–55-immunized mice. In light of these findings, we asked whether IFN-γ was required for the reduced encephalitogenicity of the weak ligand 45D in EAE. In this study, we report that immunization of mice deficient in IFN-γ or its receptor with 45D exhibit significant EAE signs compared with 45D-immunized wild-type B6 mice. Moreover, 45D-immunized IFN-γ−/− and IFN-γR−/− mice demonstrate MOG tetramer-positive CD4+ T cells within the CNS and display substantial numbers of MOG-specific CD4+ T cells in the periphery. In contrast, wild-type mice immunized with 45D exhibit reduced numbers of MOG-specific CD4+ T cells in the periphery and lack MOG tetramer- positive CD4+ T cells in the CNS. Importantly, the increased encephalitogenicity of 45D in mice lacking IFN-γ or IFN-γR was not due to deviation toward an enhanced IL-17-secreting phenotype. These findings demonstrate that IFN-γ significantly attenuates the encephalitogenicity of 45D and are the first to highlight the importance of IFN-γ signaling in setting the threshold level of responsiveness of autoreactive CD4+ T cells to weak ligands.

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Feedback Regulation of Murine Autoimmunity via Dominant Anti-Inflammatory Effects of Interferon γ

Cited by 25 publications

References 74 publications

Molecular mimics can induce a nonautoaggressive repertoire that preempts induction of autoimmunity

Molecular mimics can induce a nonautoaggressive repertoire that preempts induction of autoimmunity

HLA-DQ6 (DQB1*0601)-Restricted T Cells Protect against Experimental Autoimmune Encephalomyelitis in HLA-DR3.DQ6 Double-Transgenic Mice by Generating Anti-Inflammatory IFN-γ

Loss of IFN-γ Enables the Expansion of Autoreactive CD4+ T Cells to Induce Experimental Autoimmune Encephalomyelitis by a Nonencephalitogenic Myelin Variant Antigen

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