Characterization of MHC class-I restricted TCRαβ+ CD4− CD8− double negative T cells recognizing the gp100 antigen from a melanoma patient after gp100 vaccination

Voelkl, Simon; Moore, Tamson V.; Rehli, Michael; Nishimura, Michael I.; Mackensen, Andréas; Fischer, Karin

doi:10.1007/s00262-008-0593-3

Cited by 36 publications

(22 citation statements)

References 41 publications

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“…However, we have previously shown that Lck-recruitment to the TCR/CD3 complex by CD8 may also be essential for T-cell function [24]. The relative importance of TCR-pMHC stabilization versus signaling by CD8 has been debated [52–54,37,24]. In this study, CD8-dependence relied on the ability to bind Lck, suggesting that merely stabilizing TCR-pMHC may not permit/enhance T-cell function, but that augmenting TCR/CD3 signaling can play a critical role.…”

Section: Discussionmentioning

confidence: 99%

Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells

Spear

Wang

Foley

et al. 2017

Cancer Immunol Immunother

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T cell receptor (TCR)-pMHC affinity has been generally accepted to be the most important factor dictating antigen recognition in gene-modified T-cells. As such, there is great interest in optimizing TCR-based immunotherapies by enhancing TCR affinity to augment the therapeutic benefit of TCR gene-modified T-cells in cancer patients. However, recent clinical trials using affinity-enhanced TCRs in adoptive cell transfer (ACT) have observed unintended and serious adverse events, including death, attributed to unpredicted off-tumor or off-target cross-reactivity. It is critical to re-evaluate the importance of other biophysical, structural, or cellular factors that drive the reactivity of TCR gene-modified T-cells. Using a model for altered antigen recognition, we determined how TCR-pMHC affinity influenced the reactivity of hepatitis C virus (HCV) TCR gene-modified T-cells against a panel of naturally occurring HCV peptides and HCV-expressing tumor targets. The impact of other factors, such as TCR-pMHC stabilization and signaling contributions by the CD8 co-receptor, as well as antigen and TCR density were also evaluated. We found that changes in TCR-pMHC affinity did not always predict or dictate IFNγ release or degranulation by TCR gene-modified T-cells, suggesting that less emphasis might need to be placed on TCR-pMHC affinity as a means of predicting or augmenting the therapeutic potential of TCR gene-modified T-cells used in ACT. A more complete understanding of antigen recognition by gene-modified T-cells and a more rational approach to improve the design and implementation of novel TCR-based immunotherapies is necessary to enhance efficacy and maximize safety in patients.

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Section: Discussionmentioning

confidence: 99%

Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells

Spear

Wang

Foley

et al. 2017

Cancer Immunol Immunother

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“…The fact that OT-I cells only became DN in tissues where the antigen is expressed by parenchymal cells suggests that local presentation, perhaps in the presence of PD-L1, induces DN cell generation as a protective mechanism against self-reactive CD8 T cells. DN T cells can be found infiltrating tumors (48,49). Hence, it is possible that DN generation is facilitated in tumors as a mechanism of immune evasion (50).…”

Section: Discussionmentioning

confidence: 99%

Programmed Cell Death 1 and Helios Distinguish TCR-αβ+ Double-Negative (CD4−CD8−) T Cells That Derive from Self-Reactive CD8 T Cells

Rodríguez-Rodríguez

Apostolidis

Penaloza-MacMaster

et al. 2015

The Journal of Immunology

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TCR-αβ+ double negative (DN; CD4-CD8-) T cells represent a poorly understood cellular subset suggested to contribute to the pathogenesis of the autoimmune disease systemic lupus erythematosus. DN T cells have been proposed to derive from CD8+ cells. However, the conditions that govern the loss of CD8 expression after antigen encounter are unknown. Here we tracked the fate of CD8 T cells from transgenic TCR mice exposed to their cognate antigens as self or in the context of infection. We demonstrate that CD8 T cells lose CD8 expression and become DN only when cognate antigen is sensed as self. This process is restricted to tissues where the antigen is present. We also show that DN T cells derived from self-reactive CD8 cells express the inhibitory molecules PD-1 and Helios. These molecules identify a subset of DN T cells in normal mice. A similar population expands when CD8 T cells from repertoires enriched in self-reactive cells (Aire-deficient) are transferred into cognate hosts. Collectively, our data suggest that a subset of DN T cells, identified by the expression of PD-1 and Helios, represent self-reactive cells. Our results provide an explanation for the origin of DN T cells and introduce CD8 loss as a process associated to self-antigen encounter.

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“…Another one third of the CD30 þ T cells included CD4/CD8 DN lymphocytes. DN T cells were recently shown to exert a regulatory/tolerogenic function (21,24,25) and to be enriched in the peripheral blood of melanoma patients (26). Functional studies performed with immunosorted CD30 þ lymphocytes from the nodes of stage III melanoma patients have demonstrated that these cells are endowed with low proliferative ability and a limited capacity to produce Th1 and Th2 cytokines.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Profiling of Melanoma Sentinel Nodes Identify Patients with Poor Outcome and Reveal an Association of CD30+ T Lymphocytes with Progression

et al. 2014

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Sentinel lymph nodes set the stance of the immune system to a localized tumor and are often the first site to be colonized by neoplastic cells that metastasize. To investigate how the presence of neoplastic cells in sentinel lymph nodes may trigger pathways associated with metastatic progression, we analyzed the transcriptional profiles of archival sentinel node biopsy specimens obtained from melanoma patients. Biopsies from positive nodes were selected for comparable tumor infiltration, presence or absence of further regional node metastases, and relapse at 5-year follow-up. Unsupervised analysis of gene expression profiles revealed immune response to be a major gene ontogeny represented. Among genes upregulated in patients with progressing disease, the TNF receptor family member CD30/TNFRSF8 was confirmed in biopsy specimens from an independent group of patients. Immunohistochemical analysis revealed higher numbers of CD30 þ lymphocytes in nodes from progressing patients compared with nonprogressing patients. Phenotypic profiling demonstrated that CD30 þ lymphocytes comprised a broad population of suppressive or exhausted immune cells, such as CD4 þ Foxp3 þ or PD1 þ subpopulations and CD4 À CD8 À T cells. CD30 þ T lymphocytes were increased in peripheral blood lymphocytes of melanoma patients at advanced disease stages. Our findings reinforce the concept that sentinel nodes act as pivotal sites for determining progression patterns, revealing that the presence of CD30 þ lymphocytes at those sites associate positively with melanoma progression. Cancer Res; 74(1); 130-40. Ó2014 AACR.

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Characterization of MHC class-I restricted TCRαβ+ CD4− CD8− double negative T cells recognizing the gp100 antigen from a melanoma patient after gp100 vaccination

Cited by 36 publications

References 41 publications

Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells

Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells

Programmed Cell Death 1 and Helios Distinguish TCR-αβ+ Double-Negative (CD4−CD8−) T Cells That Derive from Self-Reactive CD8 T Cells

Transcriptional Profiling of Melanoma Sentinel Nodes Identify Patients with Poor Outcome and Reveal an Association of CD30+ T Lymphocytes with Progression

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