Immunity to Murine Prostatic Tumors: Continuous Provision of T-Cell Help Prevents CD8 T-Cell Tolerance and Activates Tumor-Infiltrating Dendritic Cells

Shafer‐Weaver, Kimberly; Watkins, Stephanie K.; Anderson, Michael J.; Draper, Lauren J.; Malyguine, Anatoli; Alvord, W. Gregory; Greenberg, Norman M.; Hurwitz, Arthur A.

doi:10.1158/0008-5472.can-08-4516

Cited by 54 publications

(76 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…First, the presence of CD4 help has been shown to inhibit induction of peripheral tolerance in CD8 1 T cells specific for self-antigens and to promote effector differentiation of CD8 1 T cells and subsequent autoimmune destruction [9,11]. Second, immunization with antigen linked to heterologous helper epitopes can restore effector function in cognate CD8 1 T cells, presumably by reversing unresponsiveness in vivo [10,37].…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…In addition to their direct effector functions, CD4 1 T cells also act as key regulators of adaptive immunity by, for instance, providing help to CD8 1 T cells and B cells. Indeed, evidence suggests that CD8 1 T-cell immunity or tolerance is directly regulated by the presence or absence of CD4 1 T-cell help [9][10][11].Therefore, understanding how to control or inactivate established populations of memory and effector CD4 1 T-cells is a key requirement for therapeutic approaches to established autoimmune and inflammatory diseases. Here, we describe studies in which we use an adoptive transfer system to investigate whether the expression of cognate antigen in steady-state DC silences memory CD4 1 T cells.…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2010

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Continuous recruitment of immune effector cells is considered crucial for effective tumor destruction 58 because immune cells become functionally quiescent within the tumor milieu. 7,21,42,59 Other reports describe diminished numbers of immune cells expressing corresponding chemokine receptors (CXCR3 ϩ and CCR5 ϩ cells) in advanced RCC disease.…”

Section: Cd209mentioning

confidence: 99%

Human Renal Cell Carcinoma Induces a Dendritic Cell Subset That Uses T-Cell Crosstalk for Tumor-Permissive Milieu Alterations

Figel

Brech

Prinz

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…The frequent observation of antigen loss from recurrent tumors (Yee et al, 2002;Dudley et al, 2005) suggests that transfer of T cells against only a single antigen may not be ideal (Yee, 2010). Although it has been shown that cotransfer of antitumor cytotoxic T lymphocytes (CTL) together with antitumor Th1 cells can improve therapy over CTL alone (Shafer-Weaver et al, 2009) to overcome T-cell tolerance, most murine models of adoptive therapy use T-cell receptor (TCR)-transgenic T cells with just a single specificity. Here, we show that control of B16ova tumors was significantly improved by cotransferring CTL targeting two different antigens (OT-I against ova and Pmel against gp100), and that, in contrast to reproducible loss of the ova antigen in response to OT-I therapy alone (Kaluza et al, 2011), combination therapy was associated with maintenance of antigen expression in escape tumors.…”

Section: Introductionmentioning

confidence: 99%

Adoptive Transfer of Cytotoxic T Lymphocytes Targeting Two Different Antigens Limits Antigen Loss and Tumor Escape

et al. 2012

View full text Add to dashboard Cite

An antitumor T-cell response can lead to tumor control without clearing all tumor cells. As long as residual tumor cells remain, there is a constant risk of escape from that T-cell response. We previously showed that adoptive transfer of anti-ova OT-I T cells into B16ova-bearing mice led to tumor regression followed by escape of tumors that had lost the ova gene, rendering the OT-I T cells ineffective. In this study, we hypothesized that simultaneous transfer of cytotoxic T lymphocytes targeted against two independent antigens would reduce selection for single-antigen-loss cells, thereby limiting tumor escape. Using OT-I and Pmel T cells to treat B16ova tumors, we found that early cotransfer could prevent tumor emergence in most mice, whereas neither T-cell specificity alone was able to do so. When combined with total body irradiation for the treatment of larger 7-day tumors, cotransfer was also better at limiting tumor recurrence, and the tumors that did escape combination therapy continued to express both target antigens. As adoptively transferred T cells also persisted in vivo, even in mice with recurrent tumors, we hypothesized that restimulation of these antitumor T cells would prolong survival of mice with recurrent tumors. Consistent with this hypothesis, administration of a low-dose regimen of cyclophosphamide following tumor escape slowed tumor growth in mice that had previously received T-cell therapy, but not in control-treated mice, an effect that was associated with increased activation of T cells in vitro by low-but not high-dose cyclophosphamide.

show abstract

Immunity to Murine Prostatic Tumors: Continuous Provision of T-Cell Help Prevents CD8 T-Cell Tolerance and Activates Tumor-Infiltrating Dendritic Cells

Abstract: We reported previously that tumor-specific CD8 + T cells (TcR-I) become tolerant in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. In this study, we show that CD4

Cited by 54 publications

References 29 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

Human Renal Cell Carcinoma Induces a Dendritic Cell Subset That Uses T-Cell Crosstalk for Tumor-Permissive Milieu Alterations

Adoptive Transfer of Cytotoxic T Lymphocytes Targeting Two Different Antigens Limits Antigen Loss and Tumor Escape

Contact Info

Product

Resources

About

Immunity to Murine Prostatic Tumors: Continuous Provision of T-Cell Help Prevents CD8 T-Cell Tolerance and Activates Tumor-Infiltrating Dendritic Cells

Abstract: We reported previously that tumor-specific CD8 + T cells (TcR-I) become tolerant in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. In this study, we show that CD4

Cited by 54 publications

References 29 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

Human Renal Cell Carcinoma Induces a Dendritic Cell Subset That Uses T-Cell Crosstalk for Tumor-Permissive Milieu Alterations

Adoptive Transfer of Cytotoxic T Lymphocytes Targeting Two Different Antigens Limits Antigen Loss and Tumor Escape

Contact Info

Product

Resources

About

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

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