Memory CD8+ T Cells Undergo Peripheral Tolerance

Kreuwel, Huub T. C.; Aung, Sandra; Silao, Cheryl; Sherman, Linda A.

doi:10.1016/s1074-7613(02)00337-0

Cited by 75 publications

(75 citation statements)

References 52 publications

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“…In contrast, our data demonstrate that the proliferation and effector function of T CM cells are suppressed by tryptophan catabolism, indicating that IDO-mediated tryptophan catabolism suppresses T CM cell function by limiting their expansion but not promoting their apoptosis. Our finding that memory CD8 ϩ cells are subject to the regulation by tryptophan catabolism supports the concept that memory CD8 ϩ T cells can undergo peripheral tolerance (41). However, our studies also show that tryptophan catabolism does not suppress T EM cell function, highlighting the distinct characteristics of T CM and T EM cells (37,42,43).…”

Section: Discussionsupporting

confidence: 85%

Suppression of Memory CD8 T Cell Generation and Function by Tryptophan Catabolism

Liu

Dai

et al. 2007

The Journal of Immunology

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Dendritic cell-derived indoleamine 2,3-dioxygenase (IDO) suppresses naive T cell proliferation and induces their apoptosis by catalyzing tryptophan, and hence is essential for the maintenance of peripheral tolerance. However, it is not known whether memory T cells are subject to the regulation by IDO-mediated tryptophan catabolism, as memory T cells respond more rapidly and vigorously than their naive counterparts and are resistant to conventional costimulatory blockade. In this study, we present the evidence that memory CD8+ T cells are susceptible to tryptophan catabolism mediated by IDO. We found that overexpression of IDO in vivo attenuated the generation of both central memory CD8+ T cells (TCM) and effector memory CD8+ T cells (TEM) while suppressing IDO activity promoted their generation. Moreover, IDO overexpression suppressed the effector function of TCM cells or TCM cell-mediated allograft rejection as well as their proliferation in vivo. Interestingly, TCM cells were resistant to apoptosis induced by tryptophan catabolism. However, IDO overexpression did not suppress the effector function of TEM cells or TEM cell-mediated allograft rejection, suggesting that TEM cells, unlike TCM cells, do not require tryptophan for their effector function once they are generated. This study provides insight into the mechanisms underlying the differential regulation of memory T cell responsiveness and has clinical implications for vaccination or tolerance induction.

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Section: Discussionsupporting

confidence: 85%

Suppression of Memory CD8 T Cell Generation and Function by Tryptophan Catabolism

Liu

Dai

et al. 2007

The Journal of Immunology

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“…Thus, different mechanisms of tolerance may be prominent depending on the nature of the active tolerogenic APC population. Intravenous administration of peptide has been reported to result in a large-scale deletion of antigen-specific CD4 1 and CD8 1 naïve T cells [30,31] and also memory CD8 1 T cells [32] reminiscent of our findings here, however, induction of unresponsiveness also appears to provide some contribution to the tolerogenic effect. Traditionally, i.v.…”

supporting

confidence: 84%

Steady‐state antigen‐expressing dendritic cells terminate CD4⁺ memory T‐cell responses

et al. 2010

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CD4 1 T cells are important effectors of inflammation and tissue destruction in many diseases of immune dysregulation. As memory T cells develop early during the preclinical stages of autoimmune and inflammatory diseases, immunotherapeutic approaches to treatment of these diseases, once established, must include the means to terminate memory T-cell responses. Traditionally, it has been considered that, due to their terminally differentiated nature, memory T cells are resistant to tolerance induction, although emerging evidence indicates that some immunotherapeutic approaches can terminate memory T-cell responses. Here, we demonstrate that CD4 1 memory T-cell responses can be terminated when cognate antigen is transgenically expressed in steady-state DC. Transfer of in-vitrogenerated CD4 1 memory T cells establishes, in nontransgenic recipients, a stable and readily recalled memory response to cognate antigen. In contrast, upon transfer to mice expressing cognate antigen targeted to DC, memory CD4 1 T cells undergo a phase of limited proliferation followed by substantial deletion, and recall responses are effectively silenced. This finding is important in understanding how to effectively apply immunotherapy to ongoing T-cell-mediated autoimmune and inflammatory diseases.Key words: CD4 1 T cells . DC . Tolerance See accompanying Commentary by Kurts IntroductionNegative selection and peripheral tolerance mechanisms jointly serve to limit the development of autoaggressive self-reactive T-cell responses. However, in autoimmune-prone individuals these control mechanisms can fail and autoimmune disease ensues. As autoimmune diseases progress, intra-and intermolecular determinant spreading occurs [1] and populations of effector and memory T cells become established. Therefore, unlike strategies directed at preventing the development of autoimmune disease, where induction of tolerance in naïve T cells may be all that is required, therapies aimed at terminating ongoing autoimmune disease must be capable of inactivating established populations of memory or activated effector T cells.Although naïve T cells are highly dependent on the presence or absence of costimulatory signals to determine the outcome of activation, costimulation appears to play little role in controlling the responses of memory and effector T cells [2,3] and these cells are considered costimulation independent. Because of this, in contrast to naïve T cells which are readily deleted or inactivated in the absence of costimulation memory T cells are widely regarded as potentially resistant to tolerance induction. If this were indeed the case, then effector and memory T cells represent a significant hurdle to therapeutic strategies aimed at treating autoimmune diseases. However, we have recently shown that memory and effector CD8 1 T cells are susceptible to tolerance induction when cognate antigen is expressed in DC and other APC types [4]. 2016The relative roles of CD4 1 and CD8 1 T cells in disease progression differ depending on the autoimmune disease bu...

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“…DEC-205 (CD205), an endocytic receptor with 10 membrane-external contiguous C-type lectin domains (6), is expressed at high levels on DCs in the T cell areas of lymphoid organs and is one of the DC surface receptors that facilitates this process (7). Like naive T cells, antigen-experienced, including memory, CD8 ϩ T cells are also subject to peripheral tolerance in response to cross-presented antigen (8). Processing and presentation of self antigens by steady-state DCs are now thought to be major components of the establishment of tolerance in the periphery.…”

mentioning

confidence: 99%

Selective delivery of β cell antigen to dendritic cells in vivo leads to deletion and tolerance of autoreactive CD8 ⁺ T cells in NOD mice

Mukhopadhaya¹,

Hanafusa²,

Jarchum³

et al. 2008

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

133

120

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Type 1 diabetes (T1D) is an autoimmune disease resulting from defects in central and peripheral tolerance and characterized by T cell-mediated destruction of islet ␤ cells. Cytotoxic CD8 ؉ T cells, reactive to ␤ cell antigens, are required for T1D development in the NOD mouse model of the disease, and CD8 ؉ T cells specific for ␤ cell antigens can be detected in the peripheral blood of T1D patients. It has been evident that in nonautoimmune-prone mice, dendritic cells (DCs) present model antigens in a tolerogenic manner in the steady state, e.g., in the absence of infection, and cause T cells to proliferate initially but then to be deleted or rendered unresponsive. However, this fundamental concept has not been evaluated in the setting of a spontaneous autoimmune disease. To do so, we delivered a mimotope peptide, recognized by the diabetogenic CD8 ؉ T cell clone AI4, to DCs in NOD mice via the endocytic receptor DEC-205. Proliferation of transferred antigen-specific T cells was initially observed, but this was followed by deletion. Tolerance was achieved because rechallenge of mice with the mimotope peptide in adjuvant did not induce an immune response. Thus, targeting of DCs with ␤ cell antigens leads to deletion of autoreactive CD8 ؉ T cells even in the context of ongoing autoimmunity in NOD mice with known tolerance defects. Our results provide support for the development of DC targeting of self antigens for treatment of chronic T cell-mediated autoimmune diseases.autoimmune disease ͉ type 1 diabetes T ype 1 diabetes (T1D) is an autoimmune disease characterized by an inability to establish and maintain tolerance to ␤ cell antigens. In diabetes-prone individuals, autoreactive T cells respond to pancreatic islet ␤ cell antigens in conjunction with costimulatory signals, promoting initial T cell activation resulting in selective expansion, differentiation, islet invasion, and ultimately destruction of ␤ cells (1). Clinically, the end result is the inability of the affected individual to produce the insulin required to properly regulate glucose metabolism. NOD mice provide a model system for T1D that shares many of the characteristics of the human disease (2). Multiple lines of investigation have demonstrated the importance of CD8 ϩ T cells in the pathogenesis of T1D in NOD mice (3). This is consistent with the detection of islet antigen-specific CD8 ϩ T cells in the peripheral blood of T1D patients (4). Using CD8 ϩ T cells derived from the islets of NOD mice, a limited number of ␤ cell antigens recognized by islet-infiltrating T cells have been identified (4). Lack of availability of a therapy for T1D other than insulin administration inspires the usage of ␤ cell antigens and epitopes targeted by T cells in T1D to develop antigen-based tolerogenic strategies.As reviewed (5), dendritic cells (DCs) in the steady state, e.g., in the absence of infection, present antigens in a tolerogenic manner and cause naive CD8 ϩ T cells to proliferate initially but then to be deleted or rendered unresponsive. The pathway by wh...

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Memory CD8+ T Cells Undergo Peripheral Tolerance

Cited by 75 publications

References 52 publications

Suppression of Memory CD8 T Cell Generation and Function by Tryptophan Catabolism

Suppression of Memory CD8 T Cell Generation and Function by Tryptophan Catabolism

Steady‐state antigen‐expressing dendritic cells terminate CD4⁺ memory T‐cell responses

Selective delivery of β cell antigen to dendritic cells in vivo leads to deletion and tolerance of autoreactive CD8 ⁺ T cells in NOD mice

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Memory CD8+ T Cells Undergo Peripheral Tolerance

Cited by 75 publications

References 52 publications

Suppression of Memory CD8 T Cell Generation and Function by Tryptophan Catabolism

Suppression of Memory CD8 T Cell Generation and Function by Tryptophan Catabolism

Steady‐state antigen‐expressing dendritic cells terminate CD4+ memory T‐cell responses

Selective delivery of β cell antigen to dendritic cells in vivo leads to deletion and tolerance of autoreactive CD8 + T cells in NOD mice

Contact Info

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About

Steady‐state antigen‐expressing dendritic cells terminate CD4⁺ memory T‐cell responses

Selective delivery of β cell antigen to dendritic cells in vivo leads to deletion and tolerance of autoreactive CD8 ⁺ T cells in NOD mice