Steady-state dendritic cells expressing cognate antigen terminate memory CD8+ T-cell responses

Kenna, Tony J.; Thomas, Ranjeny; Steptoe, Raymond J.

doi:10.1182/blood-2007-07-103200

Cited by 56 publications

(119 citation statements)

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“…2B), indicating the expansion of the OT-II population was consistent with the division indicated by CFSE dilution. As previously reported for naïve T cells [13,17,18], we have found that memory CD8 1 T cells exert a transient period of effector function upon interaction with steady-state DC [4]. To test whether this was observed here, cytokines in culture supernatant of splenocytes restimulated in vitro with or without OVA 323-339 were measured by ELISA.…”

Section: Generation Of ''Memory'' Cd4 1 T Cells In Vitrosupporting

confidence: 68%

“…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]. …”

Section: Introductionmentioning

confidence: 99%

“…No Foxp3 expression was detected in CD4 1 T cells recovered from these cultures (data not shown). Therefore, we conclude that these culture conditions generate a population of OT-II T cells phenotypically similar to central memory T cells and skewed toward a Th1 phenotype.OVA-specific memory CD4 1 T cells are activated upon transfer to mice expressing OVA in DC Using a model in which OVA expression is targeted to DC by the CD11c promoter, we have shown that steady-state presentation of OVA by OVA-expressing DC induces peripheral tolerance in naïve CD4 1 and CD8 1 T cells [13,14] and memory and effector CD8 1 T cells [4,15]. As the CD11c promoter appears to drive low-level transgene expression in CD11c int cells [16], which includes plasmacytoid DC, some activated macrophages, subsets of intraepithelial lymphocytes and NK1.1 1 cells, we previously showed that the presentation of immunogenic MHC/OVA peptide complexes was restricted to CD11c hi conventional DC [13].…”

mentioning

confidence: 99%

“…We now demonstrate that CD4 1 effector/memory T-cell responses can be also terminated by cognate antigen-expressing DC. Our demonstration here clearly indicates that the CD4 1 components of established T-cell responses are clearly susceptible to inactivation and complements our recent demonstration of a similar finding for CD8 1 T cells.Previous studies have shown that antigen-expressing DC induce peripheral tolerance in memory CD8 1 T cells through bim-dependent deletion [4]; however, residual antigen-unresponsive T cells are prominent after the deletion phase is complete and continued antigen exposure is required to maintain the unresponsive state of these cells [4]. Previous studies examining the response of naïve CD4 1 T cells to tolerogenic antigen presentation, regardless of whether antigen was targeted to DC or not, have almost universally demonstrated major contributions from both deletion and induction of unresponsiveness in the residual, nondeleted, population [13,27].…”

mentioning

confidence: 99%

“…Indeed, heterologous immunity is a hurdle for induction of transplantation tolerance [19] although, countering this, we have recently demonstrated that memory CD8 1 T-cell responses can be terminated if cognate antigen expression is targeted to DC [4]. Susceptibility of memory and effector CD4 1 T cells to peripheral tolerance induction and the possible mechanisms involved is less clear.…”

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confidence: 99%

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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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Section: Generation Of ''Memory'' Cd4 1 T Cells In Vitrosupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2010

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CD8α⁺ DC are not the sole subset cross‐presenting cell‐associated tumor antigens from a solid tumor

et al. 2010

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One of the clear paradoxes in tumor immunology is the fact that cross-presentation of cellassociated tumor antigens to CD8 1 T cells is efficient, yet CTL generation is weak, and tumors continue to grow. We examined, for the first time whether this may be due to alterations in the phenotype or function of cross-presenting DC using a solid tumor model expressing a membrane bound neo-antigen (hemagglutinin, HA). Tumor antigen was constitutively cross-presented in the tumor-draining LN throughout tumor progression by CD11c 1 DC. Further analysis revealed that both CD8a 1 and CD8a À DC subsets, but not plasmacytoid DC, were effective at cross-presenting HA tumor antigen. The proportions of DC subsets in the tumor-draining LN were equivalent to those seen in the LN of naïve mice; however, a significant increase in the expression of the potential inhibitory B7 molecule, B7-DC, was noted and appeared to be restricted to the CD8a -DC subset. Therefore LN resident CD8a 1 DC are not the sole DC subset capable of cross-presenting cell-associated tumor antigens. Migratory tumor DC subsets with altered co-stimulatory receptor expression may contribute to induction and regulation of tumor-specific responses.Key words: Cross-presentation . DC . Membrane antigen . Tumor immunology IntroductionWe have shown in previous studies that cell-associated tumor antigens are cross-presented by host APC to CD8 1 T cells [1][2][3].Despite efficient cross presentation of tumor antigens, only a weak, localized CTL response is induced and this response fails to control tumor growth [1,3,4]. Similarly in patients with cancer, tumor specific CD8 1 T cells, induced spontaneously or in response to therapy, are often detected in the tumor tissue, local draining LN and peripheral blood of cancer patients, without the induction of tumor regression [5,6]. This failure to generate strong CTL responses despite the presentation of the appropriate tumor antigen is perplexing. This lack of an effective anti-tumor CTL response is likely related to the way in which tumor antigens are presented by DC.Evidence from the field of virology, where CTL play a crucial role in controlling viral infection, demonstrates that generation of an effective CTL response requires presentation of viral antigens by activated APC, specifically DC. Notably, in this regard, cancer is generally associated with an environment that does not favor DC activation, indeed, DC found in tumor tissue and local tumordraining LN (TDLN) of cancer patients and tumor-bearing animals display a non-activated phenotype [7,8]. Thus, the manner in which tumor antigens are presented to the immune system, particularly by cross-presenting DC, may be vital in shaping the nature of tumor-specific CD8 1 T-cell responses.Though the contribution of cross-presentation to the generation of anti-tumor immunity has been challenged [9,10], there is convincing evidence that tumor antigens are efficiently crosspresented in vivo [1,[11][12][13]. DC are thought to be the principal cell type responsible for antigen c...

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Antigen presenting cell‐targeted proinsulin expression converts insulin‐specific CD8⁺ T‐cell priming to tolerance in autoimmune‐prone NOD mice

et al. 2017

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Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing pancreatic β cells. Therapies need to incorporate strategies to overcome the genetic defects that impair induction or maintenance of peripheral T-cell tolerance and contribute to disease development. We tested whether the enforced expression of an islet autoantigen in antigen-presenting cells (APC) counteracted peripheral T-cell tolerance defects in autoimmune-prone NOD mice. We observed that insulin-specific CD8 T cells transferred to mice in which proinsulin was transgenically expressed in APCs underwent several rounds of division and the majority were deleted. Residual insulin-specific CD8 T cells were rendered unresponsive and this was associated with TCR downregulation, loss of tetramer binding and expression of a range of co-inhibitory molecules. Notably, accumulation and effector differentiation of insulin-specific CD8 T cells in pancreatic lymph nodes was prominent in non-transgenic recipients but blocked by transgenic proinsulin expression. This shift from T-cell priming to T-cell tolerance exemplifies the tolerogenic capacity of autoantigen expression by APC and the capacity to overcome genetic tolerance defects.

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Steady-state dendritic cells expressing cognate antigen terminate memory CD8+ T-cell responses

Cited by 56 publications

References 50 publications

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

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

CD8α⁺ DC are not the sole subset cross‐presenting cell‐associated tumor antigens from a solid tumor

Antigen presenting cell‐targeted proinsulin expression converts insulin‐specific CD8⁺ T‐cell priming to tolerance in autoimmune‐prone NOD mice

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Steady-state dendritic cells expressing cognate antigen terminate memory CD8+ T-cell responses

Cited by 56 publications

References 50 publications

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

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

CD8α+ DC are not the sole subset cross‐presenting cell‐associated tumor antigens from a solid tumor

Antigen presenting cell‐targeted proinsulin expression converts insulin‐specific CD8+ T‐cell priming to tolerance in autoimmune‐prone NOD mice

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

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

CD8α⁺ DC are not the sole subset cross‐presenting cell‐associated tumor antigens from a solid tumor

Antigen presenting cell‐targeted proinsulin expression converts insulin‐specific CD8⁺ T‐cell priming to tolerance in autoimmune‐prone NOD mice