CD4 T Cells Play Major Effector Role and CD8 T Cells Initiating Role in Spontaneous Autoimmune Myocarditis of HLA-DQ8 Transgenic IAb Knockout Nonobese Diabetic Mice

Hayward, Sarah L.; Bautista-Lopez, Norma; Suzuki, Kunimasa; Atrazhev, Alexey; Dickie, Peter; Elliott, John F.

doi:10.4049/jimmunol.176.12.7715

Cited by 44 publications

(25 citation statements)

References 53 publications

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“…Transgenic over-expression of MCP-1 by myocardial tissue indicates that recruitment of Mø is sufficient to induce myocarditis (36). However, there are substantial numbers of T cells in the heart and lung of PD-L1−/−; MRL mice and there is a central role for T cells in other spontaneous models of myocarditis (37-39). While CD8 + T cells initiate disease, CD4 + T are the primary effectors (39).…”

Section: Discussionmentioning

confidence: 99%

Programmed Death Ligand 1 Regulates a Critical Checkpoint for Autoimmune Myocarditis and Pneumonitis in MRL Mice

Lucas

Menke

Rabacal

et al. 2008

The Journal of Immunology

171

120

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MRL/MpJ-Faslpr (MRL-Faslpr) mice develop a spontaneous T cell and macrophage-dependent autoimmune disease that shares features with human lupus. Interactions via the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway down-regulate immune responses and provide a negative regulatory checkpoint in mediating tolerance and autoimmune disease. Therefore, we tested the hypothesis that the PD-1/PD-L1 pathway suppresses lupus nephritis and the systemic illness in MRL-Faslpr mice. For this purpose, we compared kidney and systemic illness (lymph nodes, spleen, skin, lung, glands) in PD-L1 null (−/−) and PD-L1 intact (wild type, WT) MRL-Faslpr mice. Unexpectedly, PD-L1−/−;MRL-Faslpr mice died as a result of autoimmune myocarditis and pneumonitis before developing renal disease or the systemic illness. Dense infiltrates, consisting of macrophage and T cells (CD8+ > CD4+), were prominent throughout the heart (atria and ventricles) and localized specifically around vessels in the lung. In addition, once disease was evident, we detected heart specific autoantibodies in PD-L1−/−;MRL-Faslpr mice. This unique phenotype is dependent on MRL-specific background genes as PD-L1−/−;MRL+/+ mice lacking the Faslpr mutation developed autoimmune myocarditis and pneumonitis. Notably, the transfer of PD-L1−/−;MRL+/+ bone marrow cells induced myocarditis and pneumonitis in WT;MRL+/+ mice, despite a dramatic up-regulation of PD-L1 expression on endothelial cells in the heart and lung of WT;MRL+/+ mice. Taken together, we suggest that PD-L1 expression is central to autoimmune heart and lung disease in lupus-susceptible (MRL) mice.

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Section: Discussionmentioning

confidence: 99%

Programmed Death Ligand 1 Regulates a Critical Checkpoint for Autoimmune Myocarditis and Pneumonitis in MRL Mice

Lucas

Menke

Rabacal

et al. 2008

The Journal of Immunology

171

120

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“…It has been reported that CD4 + T cells are the major effector cells in myocarditis in DQ8 + NOD mice (24,39). However, the antigen specificity of the pathogenic CD4 + T cells was not defined, and the T cell assays were performed with cardiac myosin isolated from porcine heart (7,39), which predominantly expresses β-MyHC (40), so that the contribution of reactivity to α-MyHC was difficult to assess.…”

Section: Figurementioning

confidence: 99%

Impaired thymic tolerance to α-myosin directs autoimmunity to the heart in mice and humans

Lv¹,

Havari²,

Pinto³

et al. 2011

J. Clin. Invest.

184

187

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Autoimmunity has long been linked to myocarditis and its sequela, dilated cardiomyopathy, the leading causes of heart failure in young patients. However, the underlying mechanisms are poorly defined, with most clinical investigations focused on humoral autoimmunity as the target for intervention. Here, we show that the α-isoform of myosin heavy chain (α-MyHC, which is encoded by the gene Myh6) is the pathogenic autoantigen for CD4 + T cells in a spontaneous mouse model of myocarditis. Further, we found that Myh6 transcripts were absent in mouse medullary thymic epithelial cells (mTECs) and peripheral lymphoid stromal cells, which have been implicated in mediating central and peripheral T cell tolerance, respectively. Transgenic expression of α-MyHC in thymic epithelium conferred tolerance to cardiac myosin and prevented myocarditis, demonstrating that α-MyHC is a primary autoantigen in this disease process. Remarkably, we found that humans also lacked α-MyHC in mTECs and had high frequencies of α-MyHC-specific T cells in peripheral blood, with markedly augmented T cell responses to α-MyHC in patients with myocarditis. Since α-MyHC constitutes a small fraction of MyHC in human heart, these findings challenge the longstanding notion that autoimmune targeting of MyHC is due to its cardiac abundance and instead suggest that it is targeted as a result of impaired T cell tolerance mechanisms. These results thus support a role for T cell-specific therapies for myocarditis.

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“…Although CD8 1 T cells are primarily considered to play a role as effectors of target cell killing, they may also be important in disease establishment [6,7]. CD4 1 T cells, on the other hand, contribute to autoimmune and inflammatory diseases in a wide variety of ways.…”

mentioning

confidence: 99%

Steady‐state antigen‐expressing dendritic cells terminate CD4⁺ memory T‐cell responses

et al. 2010

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CD4 1 T cells are important effectors of inflammation and tissue destruction in many diseases of immune dysregulation. As memory T cells develop early during the preclinical stages of autoimmune and inflammatory diseases, immunotherapeutic approaches to treatment of these diseases, once established, must include the means to terminate memory T-cell responses. Traditionally, it has been considered that, due to their terminally differentiated nature, memory T cells are resistant to tolerance induction, although emerging evidence indicates that some immunotherapeutic approaches can terminate memory T-cell responses. Here, we demonstrate that CD4 1 memory T-cell responses can be terminated when cognate antigen is transgenically expressed in steady-state DC. Transfer of in-vitrogenerated CD4 1 memory T cells establishes, in nontransgenic recipients, a stable and readily recalled memory response to cognate antigen. In contrast, upon transfer to mice expressing cognate antigen targeted to DC, memory CD4 1 T cells undergo a phase of limited proliferation followed by substantial deletion, and recall responses are effectively silenced. This finding is important in understanding how to effectively apply immunotherapy to ongoing T-cell-mediated autoimmune and inflammatory diseases.Key words: CD4 1 T cells . DC . Tolerance See accompanying Commentary by Kurts IntroductionNegative selection and peripheral tolerance mechanisms jointly serve to limit the development of autoaggressive self-reactive T-cell responses. However, in autoimmune-prone individuals these control mechanisms can fail and autoimmune disease ensues. As autoimmune diseases progress, intra-and intermolecular determinant spreading occurs [1] and populations of effector and memory T cells become established. Therefore, unlike strategies directed at preventing the development of autoimmune disease, where induction of tolerance in naïve T cells may be all that is required, therapies aimed at terminating ongoing autoimmune disease must be capable of inactivating established populations of memory or activated effector T cells.Although naïve T cells are highly dependent on the presence or absence of costimulatory signals to determine the outcome of activation, costimulation appears to play little role in controlling the responses of memory and effector T cells [2,3] and these cells are considered costimulation independent. Because of this, in contrast to naïve T cells which are readily deleted or inactivated in the absence of costimulation memory T cells are widely regarded as potentially resistant to tolerance induction. If this were indeed the case, then effector and memory T cells represent a significant hurdle to therapeutic strategies aimed at treating autoimmune diseases. However, we have recently shown that memory and effector CD8 1 T cells are susceptible to tolerance induction when cognate antigen is expressed in DC and other APC types [4]. 2016The relative roles of CD4 1 and CD8 1 T cells in disease progression differ depending on the autoimmune disease bu...

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CD4 T Cells Play Major Effector Role and CD8 T Cells Initiating Role in Spontaneous Autoimmune Myocarditis of HLA-DQ8 Transgenic IAb Knockout Nonobese Diabetic Mice

Cited by 44 publications

References 53 publications

Programmed Death Ligand 1 Regulates a Critical Checkpoint for Autoimmune Myocarditis and Pneumonitis in MRL Mice

Programmed Death Ligand 1 Regulates a Critical Checkpoint for Autoimmune Myocarditis and Pneumonitis in MRL Mice

Impaired thymic tolerance to α-myosin directs autoimmunity to the heart in mice and humans

Steady‐state antigen‐expressing dendritic cells terminate CD4⁺ memory T‐cell responses

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CD4 T Cells Play Major Effector Role and CD8 T Cells Initiating Role in Spontaneous Autoimmune Myocarditis of HLA-DQ8 Transgenic IAb Knockout Nonobese Diabetic Mice

Cited by 44 publications

References 53 publications

Programmed Death Ligand 1 Regulates a Critical Checkpoint for Autoimmune Myocarditis and Pneumonitis in MRL Mice

Programmed Death Ligand 1 Regulates a Critical Checkpoint for Autoimmune Myocarditis and Pneumonitis in MRL Mice

Impaired thymic tolerance to α-myosin directs autoimmunity to the heart in mice and humans

Steady‐state antigen‐expressing dendritic cells terminate CD4+ memory T‐cell responses

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Steady‐state antigen‐expressing dendritic cells terminate CD4⁺ memory T‐cell responses