Systemic Administration of Agonist Peptide Blocks the Progression of Spontaneous CD8-Mediated Autoimmune Diabetes in Transgenic Mice Without Bystander Damage

Bercovici, Nadège; Heurtier, A.; Vízler, Csaba; Pardigon, Nathalie; Cambouris, Christophe; Desreumaux, Pierre; Liblau, Roland

doi:10.4049/jimmunol.165.1.202

Cited by 23 publications

(21 citation statements)

References 69 publications

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“…Second, when B25-C34 was administered systemically to young mice, before the onset of insulitis, diabetes development was suppressed. Immunoprotection after systemic high-dose administration of a CTL epitope has previously been reported in a transgenic T cell receptor (TCR) model of autoimmune diabetes (24). This effect of B25-C34 administration just before the appearance of insulitis is consistent with evidence that direct β cell recognition by MHC class I-restricted CD8 + T cells is a requirement for the onset of insulitis (31).…”

Section: Figuresupporting

confidence: 67%

Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide

Martinez¹,

Augstein²,

Moustakas³

et al. 2003

J. Clin. Invest.

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Insulin is a major target of the autoimmune response associated with destruction of pancreatic β cells in type 1 diabetes. A peptide that spans the junction of the insulin B chain and the connecting (C) peptide in proinsulin has been reported to stimulate T cells from humans at risk for type 1 diabetes and autoimmune diabetes–prone NOD mice. Here we show that proinsulin B24–C36 peptide binds to I-Ag7, the MHC class II molecule of the NOD mouse, and, after intranasal administration, induces regulatory CD4+ T cells that, in the absence of CD8+ T cells, block the adoptive transfer of diabetes. Curiously, however, intranasal B24–C36 did not inhibit development of spontaneous diabetes in treated mice. We then determined that B24–C36, and its core sequence B25–C34, bind to Kd, the NOD mouse MHC class I molecule, and elicit CD8+ CTLs. When the CD8+ T lymphocyte epitope was truncated at the C34 valine anchor residue for binding to Kd, the residual CD4+ T cell epitope, B24–C32/33, significantly inhibited diabetes development after a single intranasal dose. This study identifies a novel CTL epitope in proinsulin and demonstrates that the therapeutic potential of a “tolerogenic” autoantigen peptide can be compromised by the presence of an integral CTL epitope

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Section: Figuresupporting

confidence: 67%

Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide

Martinez¹,

Augstein²,

Moustakas³

et al. 2003

J. Clin. Invest.

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“…In fact, CD8 ϩ T-cell inactivation has been studied almost exclusively under conditions in which "inactivated" or "tolerant" CD8 ϩ T cells have differentiated from populations of naive T cells and mostly under conditions in which the influence of the "tolerising" antigen remains present, thereby preventing acquisition of memory. 6,[12][13][14][15][16] Although in vivo administration of large doses of cognate peptide induces a program of cell death in naive and postactivated antigen-specific T cells, [37][38][39][40] this process is unlikely to occur under normal physiologic conditions. Although evidence suggestive of deletion of postactivated CD4 ϩ or CD8 ϩ T cells after exposure to parenchymal antigen has been reported, 40,41 our knowledge of CD8 ϩ T-cell inactivation reflects that of naive T-cell populations, and it is unknown whether fully differentiated memory cells are susceptible to inactivation in a fashion similar to naive T cells; however, some studies conclude that memory T cells are resistant to inactivation.…”

Section: Discussionmentioning

confidence: 99%

Steady-state dendritic cells expressing cognate antigen terminate memory CD8+ T-cell responses

Kenna

Thomas

Steptoe

2008

Blood

111

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IntroductionUpon antigen stimulation, naive T cells rapidly undergo a program of expansion and terminal differentiation that leads to generation of effector and memory T cells. Whereas most of the clonally expanded T cells die, apparently through selective death of effector cells, 1,2 a small number (5%-10%) survive to generate memory cells. 2 Activation of this terminal differentiation program generates a population of cells that, compared with naive T cells, exhibit faster response kinetics, 3 increased avidity, 4 and reduced or no dependence on costimulation. 3,5 During this programming, antigenspecific T cells are therefore transformed from a naive population, possessing a highly malleable differentiation potential, to specialized committed memory and effector populations with little or no plasticity.Because of the high degree of plasticity exhibited by naive T cells, their end-stage differentiation is readily "educated" for a variety of effector functions in response to antigen-presenting cell (APC)-or environment-derived signals. In the absence of strong costimulatory signals, they are abortively activated, and naive CD8 ϩ T cells that interact with resting dendritic cells (DC) presenting cognate antigen are deleted or inactivated. 6,7 Although this is one pathway to CD8 ϩ T-cell inactivation, studies of chronic viral infection or of transgenically targeted antigen expression have indicated that persistent antigenic stimulation is another route through which naive CD8 ϩ T cells are inactivated. The molecular mechanisms that lead to, or maintain, naive CD8 ϩ T-cell inactivation appear similar for both routes, with inhibitory signaling molecules such as CD5 and programmed death 1 (PD-1) being implicated as critical regardless of whether antigen is chronically expressed or targeted to resting DC. [7][8][9][10][11] Loss of costimulation dependence and developmental plasticity implies that memory T cells will not be subject to the same regulatory checkpoints as naive T cells, and it is unclear whether traits imposed by the terminal differentiation program active in memory and effector T-cell populations render these cells impervious to cell-intrinsic inactivation. CD8 ϩ T-cell inactivation has invariably been studied under conditions in which "inactivated" or "tolerant" CD8 ϩ T cells have differentiated from populations of naive T cells 6,12 and in many systems, when the influence of "tolerising" antigen remains present 13,14 thereby preventing acquisition of memory. 15,16 Consequently, our knowledge of CD8 ϩ T-cell inactivation reflects that of naive T-cell populations, and it is unknown whether fully differentiated memory cells are susceptible to inactivation in a fashion similar to naive T cells.Memory T cells develop rapidly after antigen challenge during viral and other microbial infections. 2,17 Similarly, upon initiation of autoimmune disease, autoaggressive memory and effector T cells develop rapidly and are readily detectable early in the preclinical phase of autoimmune diseases such as type 1 diabetes...

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“…All experimental animals used in this study originated from line 21, backcrossed at least five times onto the BALB͞c background. CL4-TCR transgenic mice express a HA512-520-specific, K d -restricted T cell antigen receptor (TCR) on 90-96% of their mature CD8 ϩ T cells (24,25). Identification of the CL4-TCR transgenic mice was made by PCR (forward primer: 5Ј-GCAGGGCTGAAAGAACAGCAA-3Ј; reverse primer: 5Ј GCT-TCCTCCAGAATTTGAGGC-3Ј).…”

Section: Methodsmentioning

confidence: 99%

Enterocolitis induced by autoimmune targeting of enteric glial cells: A possible mechanism in Crohn's disease?

Cornet

Savidge

Cabarrocas

et al. 2001

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

Self Cite

289

276

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Early pathological manifestations of Crohn's disease (CD) include vascular disruption, T cell infiltration of nerve plexi, neuronal degeneration, and induction of T helper 1 cytokine responses. This study demonstrates that disruption of the enteric glial cell network in CD patients represents another early pathological feature that may be modeled after CD8 ؉ T cell-mediated autoimmune targeting of enteric glia in double transgenic mice. Mice expressing a viral neoself antigen in astrocytes and enteric glia were crossed with specific T cell receptor transgenic mice, resulting in apoptotic depletion of enteric glia to levels comparable in CD patients. Intestinal and mesenteric T cell infiltration, vasculitis, T helper 1 cytokine production, and fulminant bowel inflammation were characteristic hallmarks of disease progression. Immune-mediated damage to enteric glia therefore may participate in the initiation and͞or the progression of human inflammatory bowel disease.

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Systemic Administration of Agonist Peptide Blocks the Progression of Spontaneous CD8-Mediated Autoimmune Diabetes in Transgenic Mice Without Bystander Damage

Cited by 23 publications

References 69 publications

Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide

Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide

Steady-state dendritic cells expressing cognate antigen terminate memory CD8+ T-cell responses

Enterocolitis induced by autoimmune targeting of enteric glial cells: A possible mechanism in Crohn's disease?

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