Tissue destruction caused by cytotoxic T lymphocytes induces deletional tolerance

Parish, Ian A.; Waithman, Jason; Davey, Gayle M.; Belz, Gabrielle T.; Mintern, Justine D.; Kurts, Christian; Sutherland, Robyn M.; Carbone, Federico; Heath, William R.

doi:10.1073/pnas.0810427106

Cited by 22 publications

(26 citation statements)

References 49 publications

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“…To experimentally prove whether this state of self-tolerance could be broken by the combined Foxp3 + Treg depletion plus vaccination protocol, we crossed DEREG mice with RipOVA low mice (26) expressing OVA as neoself-antigen under control of the rat insulin promoter. It has been previously shown that transfer of OVA-specific CTL in RipOVA low mice results in the destruction of pancreatic islets and diabetes onset (46). In untreated DEREG × RipOVA low mice, we observed a rapid growth of B16-OVA melanoma, reaching a mean tumor diameter of 10 to 12 mm within 2 weeks (Fig.…”

Section: Combining Selective Foxp3mentioning

confidence: 59%

Selective Depletion of Foxp3+ Regulatory T Cells Improves Effective Therapeutic Vaccination against Established Melanoma

Klages

Mayer²,

Lahl³

et al. 2010

Cancer Research

235

194

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Section: Combining Selective Foxp3mentioning

confidence: 59%

Selective Depletion of Foxp3+ Regulatory T Cells Improves Effective Therapeutic Vaccination against Established Melanoma

Klages

Mayer²,

Lahl³

et al. 2010

Cancer Research

235

194

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“…Mice in which Em-myc-GFP or Em-myc-OVA tumors (FSC high B220 int GFP + ) had been growing for 3-5 d were treated with anti-OVA OT-I CTLs generated in vitro (22) (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

“…In vitro activation of OT-I and gBT-I ) or gBT-I cells were generated as described (22). Cultures typically contained 94-98% CD8 + Va2 + cells.…”

Section: Em-myc Lymphomasmentioning

confidence: 99%

Rapid Deletion and Inactivation of CTLs upon Recognition of a Number of Target Cells over a Critical Threshold

Prato

Zhan

Mintern

et al. 2013

The Journal of Immunology

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Initiation of CTL responses against foreign pathogens also primes anti-self CTLs. Mechanisms of CTL inactivation inhibit anti-self CTLs to prevent tissue damage. These mechanisms are exploited by pathogens and tumors to evade the immune response, and present a major hurdle to adoptive CTL therapies. It is unclear whether CTL inactivation is Ag specific and, if so, which APCs are involved. Potential candidates include the target cells themselves, dendritic cells, myeloid-derived suppressor cells, and macrophages. In this study, we show that lymphoma-specific CTLs are rapidly deleted in an Ag-specific manner after adoptive transfer into lymphoma-bearing mice, and the surviving CTLs are functionally impaired. The only APCs responsible were the target cells directly presenting Ag, notwithstanding the presence of myeloid-derived suppressor cells, and CD8+ dendritic cells cross-presenting tumor Ag. The capacity to inactivate CTLs critically depended on the number of tumor/target cells; small numbers of targets were readily killed, but a large number caused quick deletion and functional inactivation of the CTLs. Application of mild, noninflammatory, and nonlymphoablative chemotherapy to specifically reduce tumor burden before CTL injection prevented CTL deletion and inactivation and allowed eradication of tumor. Our results advocate the use of adoptive CTL therapy soon after mild chemotherapy. They also suggest a simple mechanism for Ag-specific impairment of anti-self CTLs in the face of an active anti-foreign CTL response.

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“…This is based on studies in mice expressing ovalbumin under the control of the rat insulin promoter, wherein pancreatic tissue destruction was initiated by transfer of OVA-specific CD8 effector T cells (OT-1 cells) (15). The authors found that naïve OT-I T cells underwent deletional tolerance when encountering OVA liberated and cross-presented in draining lymph nodes of these mice (15). However, pancreas destruction resolved without overt autoimmune disease (15).…”

Section: Introductionmentioning

confidence: 99%

Autoimmune Vitiligo Does Not Require the Ongoing Priming of Naive CD8 T Cells for Disease Progression or Associated Protection against Melanoma

Byrne

Zhang

Steinberg

et al. 2014

The Journal of Immunology

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Vitiligo is a CD8 T cell-mediated autoimmune disease that has been shown to promote the longevity of memory T cell responses to melanoma. However mechanisms whereby melanocyte/melanoma antigen-specific T cell responses are perpetuated in the context of vitiligo are not well understood. The present studies investigate the possible phenomenon of naïve T cell priming in hosts with melanoma-initiated, self-perpetuating, autoimmune vitiligo. Using naïve pmel (gp10025-33-specific) transgenic CD8 T cells, we demonstrate that autoimmune melanocyte destruction induces naive T cell proliferation in skin-draining lymph nodes, in an antigen-dependent fashion. These pmel T cells upregulate expression of CD44, P-selectin ligand, and granzyme B. However, they do not downregulate CD62L, nor do they acquire the ability to produce IFN-γ, indicating a lack of functional priming. Accordingly, adult thymectomized mice exhibit no reduction in the severity or kinetics of depigmentation or long-lived protection against melanoma, indicating that the continual priming of naïve T cells is not required for vitiligo or its associated anti-tumor immunity. Despite this, depletion of CD4 T cells during the course of vitiligo rescues the priming of naïve pmel T cells that are capable of producing IFN-γ and persisting as memory, suggesting an ongoing and dominant mechanism of suppression by regulatory T cells. This work reveals the complex regulation of self-reactive CD8 T cells in vitiligo, and demonstrates the overall poorly immunogenic nature of this autoimmune disease setting.

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Tissue destruction caused by cytotoxic T lymphocytes induces deletional tolerance

Cited by 22 publications

References 49 publications

Selective Depletion of Foxp3+ Regulatory T Cells Improves Effective Therapeutic Vaccination against Established Melanoma

Selective Depletion of Foxp3+ Regulatory T Cells Improves Effective Therapeutic Vaccination against Established Melanoma

Rapid Deletion and Inactivation of CTLs upon Recognition of a Number of Target Cells over a Critical Threshold

Autoimmune Vitiligo Does Not Require the Ongoing Priming of Naive CD8 T Cells for Disease Progression or Associated Protection against Melanoma

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