Contribution of TCR Signaling Strength to CD8+ T Cell Peripheral Tolerance Mechanisms

Smith, Trevor R. F.; Verdeil, Grégory; Marquardt, Kristi; Sherman, Linda A.

doi:10.4049/jimmunol.1401194

Cited by 28 publications

(29 citation statements)

References 27 publications

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“…Moreover, the expression of PD-1 on CD8 + T cells may be of less relevance in circumstances in which the targets of these CD8 + T cells do not express a PD-1 ligand, conceivably this is the case in different tumor and viral antigen systems, and probably the reason we observed an enhanced cytolytic activity in vitro from splenocytes obtained from non-tumor-bearing animals immunized with this vaccine (24). Our findings, notably in Figure 4B, are consistent with a recent report demonstrating that T cells stimulated in vitro with peptides of varying affinity can lead to different levels of PD-1 expression (34). The precise relationship between epitope-binding affinity and PD-1 expression remains unknown and is a future direction of our research.…”

Section: Discussionsupporting

confidence: 92%

“…However, these findings suggest that other methods could be explored to increase the efficacy of anti-cancer DNA vaccines. In a report from Smith and colleagues, the authors demonstrated that epitopes with slightly weakened binding affinity led to lower levels of PD-1 expression, suggesting that modifications to DNA vaccines that decrease epitope-binding affinity, while simultaneously increasing epitope presentation, might be an approach to limit PD-1 expression and increase the antitumor efficacy of DNA vaccines (34). …”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

PD-1 or PD-L1 Blockade Restores Antitumor Efficacy Following SSX2 Epitope–Modified DNA Vaccine Immunization

Rekoske

Smith

Olson

et al. 2015

Cancer Immunology Research

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DNA vaccines have demonstrated antitumor efficacy in multiple preclinical models, but low immunogenicity has been observed in several human clinical trials. This has led to many approaches seeking to improve the immunogenicity of DNA vaccines. We previously reported that a DNA vaccine encoding the cancer-testis antigen SSX2, modified to encode altered epitopes with increased MHC class I affinity, elicited a greater frequency of cytolytic, multifunctional CD8+ T cells in non-tumor-bearing mice. In this report we sought to test if this optimized vaccine resulted in increased antitumor activity in mice bearing an HLA-A2-expressing tumor engineered to express SSX2. We found that immunization of tumor-bearing mice with the optimized vaccine elicited a surprisingly inferior antitumor effect relative to the native vaccine. Both native and optimized vaccines led to increased expression of PD-L1 on tumor cells, but antigen-specific CD8+ T cells from mice immunized with the optimized construct expressed higher PD-1. Splenocytes from immunized animals induced PD-L1 expression on tumor cells in vitro. Antitumor activity of the optimized vaccine could be increased when combined with antibodies blocking PD-1 or PD-L1, or by targeting a tumor line not expressing PD-L1. These findings suggest that vaccines aimed at eliciting effector CD8+ T cells, and DNA vaccines in particular, might best be combined with PD-1 pathway inhibitors in clinical trials. This may be particularly advantageous for vaccines targeting prostate cancer, a disease for which antitumor vaccines have demonstrated clinical benefit and yet PD-1 pathway inhibitors alone have shown little efficacy to date.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

PD-1 or PD-L1 Blockade Restores Antitumor Efficacy Following SSX2 Epitope–Modified DNA Vaccine Immunization

Rekoske

Smith

Olson

et al. 2015

Cancer Immunology Research

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“…The result of an unproductive encounter, in the absence of a strong co-stimulatory signal, between an autoreactive T cell and a quiescent APC presenting cognate antigen is either the deletion of that T cell or the T cell entering an unresponsive state [2]. Factors that can influence whether deletion rather than anergy result upon T cell encounter with quiescent APC include TCR affinity, antigen density and the duration of antigen exposure [3,4]. Peripheral deletion has been well characterized using antigen-specific TCR transgenic T cells specific for model self-antigens expressed in a variety of contexts such as under the expression of the insulin promoter amongst many others [5,6].…”

Section: Deletionmentioning

confidence: 99%

“…Anergy induction can occur via signalling through alternate receptors such as Cytotoxic T lymphocyte antigen-4 (CTLA-4), which competes with CD28 for binding of its ligands CD80/CD86 [17]. For CD8 þ T cells, continual exposure to a high affinity TCR signal resulted in anergy [4,18]. Following TCR ligation with sub-optimal antigen doses, potent phosphorylation of activation-related TCR signalling molecules (e.g.…”

Section: Anergymentioning

confidence: 99%

Maintenance of peripheral tolerance to islet antigens

Hamilton‐Williams

Bergot

Reeves

et al. 2016

Journal of Autoimmunity

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“…Using clone 4 T cells, it was shown that administration of a K d -HA super agonist resulted in unresponsiveness of transferred clone 4 T cells (Smith et al, 2014). Unresponsive clone 4 T cells expressed high levels of PD-1 and the number of clone 4 T cells in spleen was similar to PBS-treated controls.…”

mentioning

confidence: 97%

Transgenic expression of proinsulin to inactivate insulin-specific CD8+ T-cell responses in autoimmune diabetes

Reeves¹

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Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic β cells. The current treatment for the fatal insulin-deficiency in T1D is injection of exogenous insulin. Despite the dramatic increase in survival from the use of exogenous insulin, complications develop from imperfect glycemic control and exogenous insulin does not rectify the underlying cause of disease, the diabetogenic autoimmune response. Hence, there is a need for an effective therapy that impedes the progress of the pathogenic autoimmune response. β cell-reactive CD8 + In the NOD mouse model of T1D, insulin is the primary β-cell antigen that elicits disease. As such, I have investigated T-cell tolerance to insulin in an adoptive transfer setting in which TCR transgenic (G9) CD8 + T cells specific for insulin B15-23 (InsB15-23) were transferred to transgenic mice over-expressing proinsulin in APC. Subsequently, I examined the effect of introducing transgenic proinsulin expression on diabetes development in wild type NOD mice.When transferred to mice transgenically expressing proinsulin, naïve G9 T cells proliferated extensively prior to undergoing rapid deletion. In proinsulin transgenic recipients, the remaining population of G9 T cells displayed reduced T-cell receptor (TCR) expression and bound less InsB15-23-loaded, H2-K d -tetramer compared to G9 T cells that had been transferred to non-transgenic NOD recipients. Interestingly, TCR down-regulation represented that which occurred for OVA-specific CD8 + T cells transferred to mice expressing OVA in APC in a non-autoimmune prone strain.Importantly, naïve G9 T cells did not expand or produce the important effector cytokine, interferon (IFN)-γ, in response to InsB15-23 immunisation after transfer to proinsulin transgenic mice. These data confirm naïve G9 T cells undergo rapid deletion and inactivation after transfer to mice transgenically-expressing proinsulin, despite genetic tolerance defects in NOD mice. Memory CD8 + T cells (Tmem) perpetuate β-cell autoimmunity and pose a distinct barrier to immunotherapy. It was pertinent to determine whether inactivation of insulin-specific CD8 + Tmem also occurs after transfer to mice expressing proinsulin in APC. To test inactivation of insulin-specific CD8 + Tmem, G9 Tmem were generated using an in vitro culture method. Cultured G9 Tmem were validated by assessing phenotypic markers and cytokine production. Similarly to naïve G9 T cells, G9 Tmem proliferated extensively and most G9 Tmem were rapidly deleted after transfer to mice overexpressing proinsulin in APC. The remaining, non-deleted population of G9 Tmem was infrequent ii and exhibited reduced TCR expression. Furthermore, G9 Tmem did not expand or produce IFN-γ in response to InsB15-23 immunisation, consistent with functional inactivation. These results demonstrate transgenic proinsulin expression in APC overcomes genetic defects in NOD mice to induce tolerance in insulin-specific CD8 + Tmem.From the data described above, transgenic proinsulin expression is tolerogenic for in...

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Contribution of TCR Signaling Strength to CD8+ T Cell Peripheral Tolerance Mechanisms

Cited by 28 publications

References 27 publications

PD-1 or PD-L1 Blockade Restores Antitumor Efficacy Following SSX2 Epitope–Modified DNA Vaccine Immunization

PD-1 or PD-L1 Blockade Restores Antitumor Efficacy Following SSX2 Epitope–Modified DNA Vaccine Immunization

Maintenance of peripheral tolerance to islet antigens

Transgenic expression of proinsulin to inactivate insulin-specific CD8+ T-cell responses in autoimmune diabetes

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