Dominant CTL-inducing epitopes on GAD65 are adjacent to or overlap with dominant Th-inducing epitopes

Busick, Rhea Y.; Aguilera, Carlos; Quinn, Anthony

doi:10.1016/j.clim.2006.10.008

Cited by 7 publications

(21 citation statements)

References 69 publications

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“…Previously, we have reported that peptide 546-554 is a pathogenic CTL-inducing epitope of GAD65 [26,28]. GAD65546-554-specific CTL are detected in naïve NOD mice, produce inflammatory cytokines IFNγ and TNFα upon culture with cognate antigen [26], and transfer islet inflammation [28]. Importantly, subsequent work has confirmed that GAD65-specific CTL, including those specific for p546-554, have diabetogenic potential [29].…”

Section: Introductionmentioning

confidence: 85%

“…GAD65546-554-specific CTL lines and clones were generated as previously described [28] following immunization of NOD mice with GAD65546-554 (SYQPLGDKV) (Invitrogen, Carlsbad, CA). NP147-specific CTL were generated by immunization of NOD mice with the K d -binding peptide, 147-155 (TYQRTRALV), from the nucleoprotein (NP) of influenza.…”

Section: Mice and Cellsmentioning

confidence: 99%

“…T cell responses to GAD65 are detectable in the spleens of prediabetic NOD mice and in the peripheral blood of humans with T1D prior to the onset of overt hyperglycemia [23,24], suggesting that GAD65 autoimmunity is important in the initial and later stages of disease. While the CD4 + responses to GAD65 determinants have been well characterized [23][24][25], less is known about the CTL response to GAD65 [26][27][28][29]. Previously, we have reported that peptide 546-554 is a pathogenic CTL-inducing epitope of GAD65 [26,28].…”

Section: Introductionmentioning

confidence: 99%

“…While the CD4 + responses to GAD65 determinants have been well characterized [23][24][25], less is known about the CTL response to GAD65 [26][27][28][29]. Previously, we have reported that peptide 546-554 is a pathogenic CTL-inducing epitope of GAD65 [26,28]. GAD65546-554-specific CTL are detected in naïve NOD mice, produce inflammatory cytokines IFNγ and TNFα upon culture with cognate antigen [26], and transfer islet inflammation [28].…”

Section: Introductionmentioning

confidence: 99%

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GAD65-Specific Cytotoxic T Lymphocytes Mediate Beta-Cell Death and Loss of Function

Rasche

Busick²,

Quinn³

2009

Rev Diabet Stud

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■ AbstractAutoimmunity to islet cell antigens like glutamic acid decarboxylase 65kD (GAD65) is associated with the destruction of insulin-producing β-cells and progression to type 1 diabetes (T1D) in NOD mice and humans. T cell responses to GAD65 are detectable in the spleen of prediabetic NOD mice and in the peripheral blood of humans prior to the onset of overt hyperglycemia. Previous findings from our lab revealed that GAD65 546-554 -specific cytotoxic T lymphocytes (CTL) are present in naïve NOD mice and are able to induce islet inflammation upon adoptive transfer into NOD.scid recipients. Additionally, we found that professional antigen-presenting cells (APC) generate the p546-554 epitope from a soluble GAD65 fragment, p530-554, and from GAD65 released by injured β-cells in vivo. Here, we report that the GAD65 fragment p546-554 is a dominant CTL-inducing epitope which is naturally processed and presented by a GAD65-expressing β-cell line. Further, coculture of GAD65 546-554 -specific CTL with the β-cells leads to a reduction in insulin production and the induction of perforin-mediated cell death. Collectively, these findings support a role for the cross-presentation of GAD65 antigen in the priming and enhancement of dominant GAD65-specific CTL responses, which can directly target β-cells that display GAD65 epitopes.

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Section: Introductionmentioning

confidence: 85%

Section: Mice and Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

GAD65-Specific Cytotoxic T Lymphocytes Mediate Beta-Cell Death and Loss of Function

Rasche

Busick²,

Quinn³

2009

Rev Diabet Stud

Self Cite

View full text Add to dashboard Cite

show abstract

“…[20][21][22][23] CD8 T cells reactive to glutamic acid decarboxylase (GAD65)-especially GAD65, amino acids 546-554 (GAD65 546-554 )-have also been identified in the NOD mouse. 26,27 Immune responses to proinsulin are necessary for IGRP-reactive CTLs to expand 28,29 and to cause diabetes. Therefore, early immunological intervention selectively targeting dominant CTL clones may arrest b cell destruction and inhibit, or entirely prevent, the onset of disease.…”

Section: Introductionmentioning

confidence: 99%

Adoptive Transfer of mRNA-Transfected T Cells Redirected against Diabetogenic CD8 T Cells Can Prevent Diabetes

et al. 2017

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Noncontiguous T cell epitopes in autoimmune diabetes: From mice to men and back again

Amdare

Purcell

DiLorenzo

2021

Journal of Biological Chemistry

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show abstract

Dominant CTL-inducing epitopes on GAD65 are adjacent to or overlap with dominant Th-inducing epitopes

Cited by 7 publications

References 69 publications

GAD65-Specific Cytotoxic T Lymphocytes Mediate Beta-Cell Death and Loss of Function

GAD65-Specific Cytotoxic T Lymphocytes Mediate Beta-Cell Death and Loss of Function

Adoptive Transfer of mRNA-Transfected T Cells Redirected against Diabetogenic CD8 T Cells Can Prevent Diabetes

Noncontiguous T cell epitopes in autoimmune diabetes: From mice to men and back again

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