The molecular signature of CD8+ T cells undergoing deletional tolerance

Parish, Ian A.; Rao, Sudha; Smyth, Gordon K.; Juelich, Torsten; Denyer, Gareth; Davey, Gayle M.; Strasser, Andreas; Heath, William R.

doi:10.1182/blood-2008-10-185223

Cited by 84 publications

(109 citation statements)

References 65 publications

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“…In contrast, the CD8 C BTLA ¡ TIL subset consisted of more late-stage differentiated T EM and T EMRA TIL that were less responsive to IL-2 or TCR signals and exhibited a molecular signature of T-cell deletion. 13,14 We also found that the ligation of BTLA on CD8…”

Section: Introductionmentioning

confidence: 81%

BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties

Haymaker

Ritthipichai

et al. 2015

OncoImmunology

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Section: Introductionmentioning

confidence: 81%

BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties

Haymaker

Ritthipichai

et al. 2015

OncoImmunology

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“…Bim is the most important BH3-only protein in the hematopoietic system. In lymphocytes, Bimdependent apoptosis is associated with an induction of Bim protein (T cells, 19 Bim protein levels, at least at early stages when the Bim effect is most obvious (see below, Figure 2). The apoptosisassociated induction of Bim (and of Puma) can be driven by increased FOXO3a-dependent transcription.…”

Section: Resultsmentioning

confidence: 99%

Molecular analysis of neutrophil spontaneous apoptosis reveals a strong role for the pro-apoptotic BH3-only protein Noxa

et al. 2011

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International audienceNeutrophils enter the peripheral blood from the bone marrow and die after a short time. Molecular analysis of spontaneous neutrophil apoptosis is difficult as these cells die rapidly and cannot be easily manipulated. We use conditional Hoxb8-expression to generate mouse neutrophils and test the regulation of apoptosis by extensive manipulation of Bcl-2 family proteins. Spontaneous apoptosis was preceded by down-regulation of anti-apoptotic Bcl-2 proteins. Loss of the pro-apoptotic BH3-only protein Bim gave some protection but only neutrophils deficient in both BH3-only proteins, Bim and Noxa were strongly protected against apoptosis. The function of Noxa was neutralization of Mcl-1 in neutrophils and progenitors. Loss of Bim and Noxa preserved neutrophil function in culture and apoptosis-resistant cells remained in circulation in mice. Apoptosis regulated by Bim and the Noxa-driven loss of Mcl-1 is thus the final step in neutrophil differentiation and is required for the termination of neutrophil function and neutrophil-dependent inflammation

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“…3B), suggesting that MR-mediated T-cell impairment shares mechanisms operative in T-cell tolerance. Next, we applied a combined approach to identify and prioritize candidate effector molecules responsible for MR-mediated T-cell impairment as defined by differential expression at least at one time point (first criterion), being part of the tolerance gene set (second criterion), and being part of a set of genes (n = 45) that were previously associated with T-cell anergy or tolerance (third criterion) (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). For genes within the intersection of these three gene groups, a sum rank was determined based on most significant differential expression (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4

Schuette

Embgenbroich

Ulas

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The mannose receptor (MR) is an endocytic receptor involved in serum homeostasis and antigen presentation. Here, we identify the MR as a direct regulator of CD8 + T-cell activity. We demonstrate that MR expression on dendritic cells (DCs) impaired T-cell cytotoxicity in vitro and in vivo. This regulatory effect of the MR was mediated by a direct interaction with CD45 on the T cell, inhibiting its phosphatase activity, which resulted in up-regulation of cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) and the induction of T-cell tolerance. Inhibition of CD45 prevented expression of B-cell lymphoma 6 (Bcl-6), a transcriptional inhibitor that directly bound the CTLA-4 promoter and regulated its activity. These data demonstrate that endocytic receptors expressed on DCs contribute to the regulation of T-cell functionality.T he mannose receptor (MR) is an endocytic receptor belonging to the C-type lectin family and is expressed by distinct populations of dendritic cells (DCs), macrophages, and endothelial cells (1). It consists of an N-terminal cysteine-rich domain (CR), a fibronectin type II (FN II) domain, eight C-type lectinlike domains (CTLDs), a transmembrane region, and a short intracellular region. The CTLDs of the MR can bind to glycoconjugates terminated in mannose, fucose, or glucose. Despite the presence of eight CTLDs, only CTLD4 is responsible for carbohydrate binding. Additionally, the MR can bind to sulfated carbohydrates via its CR and to collagen via its FN II domain (1).In a previous study, we demonstrated that antigens internalized by the MR are processed specifically for cross-presentation (2). The correlation between the MR and cross-presentation offered the possibility that antigens targeted toward the MR could induce potent cytotoxic T-cell responses. Because the induction of a strong cytotoxic T-cell response against tumor-specific antigens is a crucial process in many tumor vaccination strategies, antigen targeting toward the MR seemed to be a promising approach. However, in in vivo tumor models, antigen targeting toward the MR did not result in a strong cytotoxic T-cell response but, instead, led to the induction of antigen-specific T-cell tolerance (3, 4). Therefore, we analyzed whether the MR has a regulatory effect on the induction of immune responses by means distinct from antigen uptake and presentation, and we investigated a direct influence of the MR on T-cell activation. We could demonstrate that the presence of the MR on the antigen-presenting cell (APC) directly impairs the cytotoxic activity of T cells in vitro and in vivo. We showed that this effect was due to a direct interaction of the MR with CD45 on the T-cell surface. This interaction inhibited CD45 activity and resulted in the up-regulation of the inhibitory molecule cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4), which was responsible for the impaired cytotoxic activity of the T cells. ResultsThe Presence of the MR on DCs Reduces Cytotoxic Activity of CD8 + T Cells. To investigate whether the MR influences T-cell ...

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The molecular signature of CD8+ T cells undergoing deletional tolerance

Cited by 84 publications

References 65 publications

BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties

BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties

Molecular analysis of neutrophil spontaneous apoptosis reveals a strong role for the pro-apoptotic BH3-only protein Noxa

Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4

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