Death of peripheral CD8<sup>+</sup> T cells in the absence of MHC class I is Fas‐dependent and not blocked by Bcl‐x<sub>L</sub>

Markiewicz, Mary A.; Brown, Ian E.; Gajewski, Thomas F.

doi:10.1002/eji.200324273

Cited by 19 publications

(21 citation statements)

References 19 publications

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“…S1C). This is in sharp contrast to recently reported results for CD8 T cells, which can survive by means of contact with MHCI expressed by either hematopoietic or stromal compartments (31), and can be rendered tolerant by specific antigen presented by radioresistant LN stroma (32).…”

Section: Discussioncontrasting

confidence: 99%

Langerhans cells are precommitted to immune tolerance induction

Shklovskaya¹,

O’Sullivan

et al. 2011

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

150

135

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Antigen-dependent interactions between T lymphocytes and dendritic cells (DCs) can produce two distinct outcomes: tolerance and immunity. It is generally considered that all DC subsets are capable of supporting both tolerogenic and immunogenic responses, depending on their exposure to activating signals. Here, we tested whether epidermal Langerhans cells (LCs) can support immunogenic responses in vivo in the absence of antigen presentation by other DC subsets. CD4 T cells responding to antigen presentation by activated LCs initially proliferated but then failed to differentiate into effector/memory cells or to survive long term. The tolerogenic function of LCs was maintained after exposure to potent adjuvants and occurred despite up-regulation of the costimulatory molecules CD80, CD86, and IL-12, but was consistent with their failure to translocate the NF-κB family member RelB from the cytoplasm to the nucleus. Commitment of LCs to tolerogenic function may explain why commensal microorganisms expressing Toll-like receptor (TLR) ligands but confined to the skin epithelium are tolerated, whereas invading pathogens that breach the epithelial basement membrane and activate dermal DCs stimulate a strong immune response.D endritic cells (DCs) initiate adaptive immune responses by priming antigen-specific T cells in secondary lymphoid organs. After sampling antigens in peripheral tissues, DCs migrate to lymph nodes (LN), where they present antigenic peptides bound to major histocompatibility (MHC) molecules (1). Epidermal Langerhans cells (LCs) have long been regarded as prototypic DCs, highly active in antigen uptake and rapidly acquiring potent costimulatory capacity after in vitro culture (2). Recently, the immunogenicity of LCs has been questioned on the basis of findings in several in vivo experimental models. During herpes viral infection of the skin, migrated LCs isolated from draining LN (dLN) were unable to induce proliferation of virusspecific CD8 T cells in vitro (3). In LC ablation models, positive (4, 5), negative (6-8), and redundant (9) contributions of LCs to contact hypersensitivity responses were reported. The current lack of consensus regarding LC function may relate, at least in part, to the difficulties in determining the contribution of a relatively small number of LCs to responses driven primarily by non-LC DC subsets in cutaneous LN (cLN).Here we directly tested the in vivo function of LCs, using a previously described bone marrow (BM) chimeric mouse model in which only LCs can present specific antigen to CD4 T cells (10). In this model, all DC subsets express MHC class II IA molecules but only LCs express MHC class II IE, which is absolutely required to present moth cytochrome C peptide (pMCC) to 5C.C7 T-cell receptor (TCR) transgenic T cells (11,12). The response of adoptively transferred 5C.C7 CD4 T cells can thus be used as a readout for LC function. We compared 5C.C7 T-cell responses to LCs with those in chimeras expressing IE on nonepidermal DCs or all DC subsets, immunizing with peptide o...

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Section: Discussioncontrasting

confidence: 99%

Langerhans cells are precommitted to immune tolerance induction

Shklovskaya¹,

O’Sullivan

et al. 2011

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

150

135

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“…The requirement for MHC in survival of naïve CD8 T cells has since been confirmed in both transgenic and polyclonal T cells (see for example (23,24)). An intriguing observation is that CD8 T cells do not die immediately after transfer to MHCdeficient environments.…”

Section: Self-mhc and Cd8 T Cell Homeostasismentioning

confidence: 96%

“…An intriguing observation is that CD8 T cells do not die immediately after transfer to MHCdeficient environments. Rather, they survive and can respond to accessory cell signals for at least one week (23), and their eventual death is dependent on expression of the death factor protein Fas and its interaction with Fas ligand (FasL) (24). Rocha et al showed that survival of naïve CD8 cells was not only dependent on MHC expression, but also required the right MHC-restricting element (25).…”

Section: Self-mhc and Cd8 T Cell Homeostasismentioning

confidence: 99%

Negative regulators in homeostasis of naïve peripheral T cells

2008

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It is now apparent that naïve peripheral T cells are a dynamic population where active processes prevent inappropriate activation while supporting survival. The process of thymic education makes naïve peripheral T cells dependent on interactions with self-MHC for survival. However, as these signals can potentially result in inappropriate activation, various non-redundant, intrinsic negative regulatory molecules including Tob, Nfatc2, and Smad3 actively enforce T cell quiescence. Interactions among these pathways are only now coming to light and may include positive or negative crosstalk. In the case of positive crosstalk, self-MHC initiated signals and intrinsic negative regulatory factors may cooperate to dampen T cell activation and sustain peripheral tolerance in a binary fashion (on-off). In the case of negative crosstalk, self-MHC signals may promote survival through partial activation while intrinsic negative regulatory factors act as rheostats to restrain cell cycle entry and prevent T cells from crossing a threshold that would break tolerance. KeywordsT cells; MHC; sensitization; desensitization; cell cycle; negative regulation; tolerance The Influence of Self-MHC in T-Cell Quiescence and Survival Self-MHC and naïve T cell survivalThe role of self-peptides complexed to major histocompatibility complex proteins (self-MHC) to maintain homeostasis of naïve T cells has been the subject of extensive investigation over the past decade. This work has revealed apparent differences in the sensitivity of different T cell subsets to the absence of self-MHC. Perhaps the most informative experiments have attempted to characterize the expansion of peripheral lymphocytes in MHC-replete or MHCdeficient lymphopenic environments. The idea that "space" in the peripheral lymphoid organs drove lymphocyte proliferation arose from the observation that under conditions of lymphopenia such as those produced by non-myeloablative, lymphodepleting regimens in humans or mice, or under conditions encountered by adoptively transferred lymphocytes or bone marrow cells into lymphopenic hosts, T cells would expand without exogenous antigens. It is now apparent that this "lymphopenia-induced proliferation" or "homeostatic proliferation" (HP) results not only from "space", but also from interactions of T cell receptors (TCR) with self-MHC, and from lessened competition for cytokines including interleukin-7 (IL-7), or in some cases, Unlike HP in MHC-replete hosts, a majority of naïve T cells die or make at most a few divisions if the lymphopenic periphery is devoid of MHC (16-21), a result consistent with the premise that HP is itself partly driven by recognition of self-MHC complexes. Both CD4 and CD8 T cells undergo HP, although CD4 T cells expand less in response to MHC and CD8 T cells are more sensitive to its absence. In fact, while the requirement for self-MHC in naïve CD8 T cell survival is generally accepted (although it may not apply to all CD8 T cell subsets) (22), the delayed erosion of naïve CD4 T cells in lymphopenic h...

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“…Tonic TCR engagement is generated by the interaction of the TCR with weakly reactive self-peptides (3). Survival of quiescent CD8 T cells requires MHC class I-TCR engagement, which is indicated by dwindling numbers of naïve CD8 T cells after transfer into MHC class I-deficient mice (4,5). In addition, long-term (but not short-term) survival of CD4 T cells requires the presence of MHC class II (6).…”

mentioning

confidence: 99%

Basal NF-κB controls IL-7 responsiveness of quiescent naïve T cells

Miller

Mashayekhi

Chen

et al. 2014

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

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T cells are essential for immune defenses against pathogens, such that viability of naïve T cells before antigen encounter is critical to preserve a polyclonal repertoire and prevent immunodeficiencies. The viability of naïve T cells before antigen recognition is ensured by IL-7, which drives expression of the prosurvival factor Bcl-2. Quiescent naïve T cells have low basal activity of the transcription factor NF-κB, which was assumed to have no functional consequences. In contrast to this postulate, our data show that basal nuclear NF-κB activity plays an important role in the transcription of IL-7 receptor α-subunit (CD127), enabling responsiveness of naïve T cells to the prosurvival effects of IL-7 and allowing T-cell persistence in vivo. Moreover, we show that this property of basal NF-κB activity is shared by mouse and human naïve T cells. Thus, NF-κB drives a distinct transcriptional program in T cells before antigen encounter by controlling susceptibility to IL-7. Our results reveal an evolutionarily conserved role of NF-κB in T cells before antigenic stimulation and identify a novel molecular pathway that controls T-cell homeostasis.urvival of naïve quiescent T cells is essential to maintain a pool of polyclonal T cells ready for activation by their cognate antigen. On egress from the thymus, survival of peripheral naïve T cells (CD4 + CD44 lo and CD8 + CD44 lo ) depends on intermittent tonic engagement of the T-cell receptor (TCR) and signaling by the cytokine IL-7 (1, 2). Tonic TCR engagement is generated by the interaction of the TCR with weakly reactive self-peptides (3). Survival of quiescent CD8 T cells requires MHC class I-TCR engagement, which is indicated by dwindling numbers of naïve CD8 T cells after transfer into MHC class I-deficient mice (4, 5). In addition, long-term (but not short-term) survival of CD4 T cells requires the presence of MHC class II (6).IL-7 is important for survival and homeostatic proliferation of naïve T cells, which is shown by reduced recovery of naïve T cells transferred into IL-7 −/− mice (7, 8) and impaired survival and homeostatic proliferation of T cells from IL-7 receptor α-subunit (IL-7Rα) -deficient mice (9, 10). The receptor for IL-7 is a heterodimer consisting of the IL-7Rα (CD127) and common γ-chain receptor (γ c ; CD132) subunits. Triggering of IL-7R activates Stat5 through Jak1/Jak3 (11) and the PI3K/Akt/mTOR axis (12). IL-7-mediated survival involves up-regulation of the prosurvival factors Bcl-2 and Mcl-1 as well as reduction of proapoptotic molecules Bax, Bad, and Bim (13). Interestingly, IL-7 negatively regulates the expression of its receptor, promoting endocytosis, degradation, and the transcriptional inhibition of Il7r expression (11,14). This milieu enables a pool of T cells that have not yet encountered IL-7 to be preferentially responsive to limiting concentrations of this cytokine. Several transcription factors are involved in the control of Il7r expression in T cells, including positive regulation by GA binding protein, glucocorticoid receptor,...

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Death of peripheral CD8⁺ T cells in the absence of MHC class I is Fas‐dependent and not blocked by Bcl‐x_L

Cited by 19 publications

References 19 publications

Langerhans cells are precommitted to immune tolerance induction

Langerhans cells are precommitted to immune tolerance induction

Negative regulators in homeostasis of naïve peripheral T cells

Basal NF-κB controls IL-7 responsiveness of quiescent naïve T cells

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Death of peripheral CD8+ T cells in the absence of MHC class I is Fas‐dependent and not blocked by Bcl‐xL

Cited by 19 publications

References 19 publications

Langerhans cells are precommitted to immune tolerance induction

Langerhans cells are precommitted to immune tolerance induction

Negative regulators in homeostasis of naïve peripheral T cells

Basal NF-κB controls IL-7 responsiveness of quiescent naïve T cells

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Product

Resources

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Death of peripheral CD8⁺ T cells in the absence of MHC class I is Fas‐dependent and not blocked by Bcl‐x_L