Deletion of Naive CD8 T Cells Requires Persistent Antigen and Is Not Programmed by an Initial Signal from the Tolerogenic APC

Redmond, William L.; Hernandez, Javier; Sherman, Linda A.

doi:10.4049/jimmunol.171.12.6349

Cited by 36 publications

(32 citation statements)

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“…Surprisingly, we found that a significant number of cells could survive following their initial exposure to Ag and that activation with quiescent APCs did not result in complete deletion (9). These data suggested that during tolerance induction, deletion of naive CD8 T cells was not programmed during the initial stimulatory event and that additional exposure to Ag was required to achieve complete clonal deletion.…”

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confidence: 56%

Distinct Requirements for Deletion versus Anergy during CD8 T Cell Peripheral Tolerance In Vivo

Redmond

Marincek

Sherman

2005

The Journal of Immunology

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Activation of naive T cells by quiescent APCs results in tolerance through deletion and anergy. The underlying basis for these distinct fates is unclear. Using clone 4 TCR transgenic animals as a source of naive CD8 T cells, we examined the requirements for peripheral deletion in vivo. Our results demonstrate that independent of the amount of Ag used for stimulation, a single dose was insufficient to achieve complete clonal deletion. Instead, further antigenic exposure was required to completely eliminate all of the activated T cells. Additionally, consecutive stimulations with low doses of Ag were highly effective in promoting deletion. In contrast, although stimulation with high doses of Ag initially led to the apoptosis of many of the activated T cells, it induced hyporesponsiveness in a portion of the responding cells, thereby sparing them from further activation and deletion. These data explain why some conditions promote tolerance through clonal deletion whereas others promote anergy. Furthermore, these data provide a framework to devise protocols for effective deletion of potentially autoreactive T cells.

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confidence: 56%

Distinct Requirements for Deletion versus Anergy during CD8 T Cell Peripheral Tolerance In Vivo

Redmond

Marincek

Sherman

2005

The Journal of Immunology

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“…In contrast, naive clone 4 T cells do not spontaneously acquire effector functions or induce diabetes following their adoptive transfer into InsHA mice (Fig. 2D and Table I) (8,41). This has allowed us to observe an effect of Bcl-2 over-expression in promoting acquisition of effector function.…”

Section: Discussionmentioning

confidence: 79%

The Apoptotic Pathway Contributing to the Deletion of Naive CD8 T Cells during the Induction of Peripheral Tolerance to a Cross-Presented Self-Antigen

Redmond

Wei

Kreuwel

et al. 2008

The Journal of Immunology

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The maintenance of T cell tolerance in the periphery proceeds through several mechanisms, including anergy, immuno-regulation, and deletion via apoptosis. We examined the mechanism underlying the induction of CD8 T cell peripheral tolerance to a self-Ag expressed on pancreatic islet β-cells. Following adoptive transfer, Ag-specific clone 4 T cells underwent deletion independently of extrinsic death receptors, including Fas, TNFR1, or TNFR2. Additional experiments revealed that the induction of clone 4 T cell apoptosis during peripheral tolerance occurred via an intrinsic death pathway that could be inhibited by overexpression of Bcl-2 or targeted deletion of the proapoptotic molecule, Bim, thereby resulting in accumulation of activated clone 4 T cells. Over-expression of Bcl-2 in clone 4 T cells promoted the development of effector function and insulitis whereas Bim−/− clone 4 cells were not autoaggressive. Examination of the upstream molecular mechanisms contributing to clone 4 T cell apoptosis revealed that it proceeded in a p53, E2F1, and E2F2-independent manner. Taken together, these data reveal that initiation of clone 4 T cell apoptosis during the induction of peripheral tolerance to a cross-presented self-Ag occurs through a Bcl-2-sensitive and at least partially Bim-dependent mechanism.

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“…These data support previous studies stating peripheral tolerance induction requires continual antigen stimulation. 24,25 However, the previous studies could not assess the activation status of responding cells without amplification and they relied on in vitro selection and adoptive transfer to assess the necessity for continued antigen expression. The POET-I model provided an unique opportunity to assess reactive cells within the host through castration and the resulting loss of high level antigen expression.…”

Section: Discussionmentioning

confidence: 99%

Deletion is neither sufficient nor necessary for the induction of peripheral tolerance in mature CD8⁺ T cells

Lees¹,

Charbonneau²,

Swanson

et al. 2006

Immunology

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SummaryPrevious reports have demonstrated clonal deletion of CD8 + T cells during peripheral tolerance induction to tissue antigens. However, direct evidence demonstrating a causal connection between deletion and tolerance has not been reported because of model limitations in which the tissue antigens were expressed in vital organs. Thus, studies were initiated in a mouse model where expression of a membrane-bound ovalbumin fusion protein (mOVA) was driven by a prostate specific androgen regulated probasin promotor, providing restricted expression in a non-vital organ where antigen levels can be abrogated through androgen deprivation. Adoptive transfer of mOVA specific CD8 + T cells (OT-I) was used to assess the development of peripheral tolerance. Proliferation of OT-I cells was observed, as was partial deletion of transferred OT-I cells. Although deletion occurred, the long-term persistence of a stable level of OT-I cells was observed. Importantly, the persistent OT-I cells lost antigen responsiveness within 3 weeks of transfer. Castration resulted in loss of highlevel prostate mOVA expression, with a resultant abrogation of tolerance induction, but surprisingly did not affect the deletion rate of OT-I cells.In contrast, abrogation of deletion through the adoptive transfer of OT-I cells from third generation CD95-deficient mice had no effect on tolerance induction. These data demonstrate the necessity for continued expression of tissue antigen throughout the establishment of peripheral tolerance. Furthermore, these findings demonstrate that deletion is neither sufficient nor required for CD8 + T-cell tolerance to tissue antigens, suggesting that regulatory events independent of deletion are necessary for peripheral tolerance induction to prostate antigens.Keywords: tolerance/suppression/anergy; CTL; cellular activationAbbreviations: mOVA, membrane-bound transferrin-receptor/ovalbumin fusion protein; POET, prostate ovalbumin expressing transgenic mice.

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Deletion of Naive CD8 T Cells Requires Persistent Antigen and Is Not Programmed by an Initial Signal from the Tolerogenic APC

Cited by 36 publications

References 35 publications

Distinct Requirements for Deletion versus Anergy during CD8 T Cell Peripheral Tolerance In Vivo

Distinct Requirements for Deletion versus Anergy during CD8 T Cell Peripheral Tolerance In Vivo

The Apoptotic Pathway Contributing to the Deletion of Naive CD8 T Cells during the Induction of Peripheral Tolerance to a Cross-Presented Self-Antigen

Deletion is neither sufficient nor necessary for the induction of peripheral tolerance in mature CD8⁺ T cells

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Deletion of Naive CD8 T Cells Requires Persistent Antigen and Is Not Programmed by an Initial Signal from the Tolerogenic APC

Cited by 36 publications

References 35 publications

Distinct Requirements for Deletion versus Anergy during CD8 T Cell Peripheral Tolerance In Vivo

Distinct Requirements for Deletion versus Anergy during CD8 T Cell Peripheral Tolerance In Vivo

The Apoptotic Pathway Contributing to the Deletion of Naive CD8 T Cells during the Induction of Peripheral Tolerance to a Cross-Presented Self-Antigen

Deletion is neither sufficient nor necessary for the induction of peripheral tolerance in mature CD8+ T cells

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Deletion is neither sufficient nor necessary for the induction of peripheral tolerance in mature CD8⁺ T cells