Does T-cell tolerance require a dedicated antigen-presenting cell?

Nature ◽  
1989 ◽  
Vol 338 (6210) ◽  
pp. 74-76 ◽  
Author(s):  
Polly Matzinger ◽  
Sylvie Guerder
10.1038/nm962 ◽  
2003 ◽  
Vol 9 (12) ◽  
pp. 1469-1476 ◽  
Author(s):  
Douglas G Millar ◽  
Kristine M Garza ◽  
Bernhard Odermatt ◽  
Alisha R Elford ◽  
Nobuyuki Ono ◽  
...  

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2391-2391
Author(s):  
Hongwei Wang ◽  
Aung Naing ◽  
Fengdong Cheng ◽  
Pedro Horna ◽  
Ildelfonso Suarez ◽  
...  

Abstract Professional antigen-presenting cells (APCs) play an important role in the initiation of antigen-specific T-cell responses. The demonstration that these cells are also required for the induction of T-cell tolerance, placed APCs at the crossroads of immune activation versus immune tolerance. Recent studies have demonstrated that the inflammatory status of the APC at the time of antigen presentation is the central determinant of T-cell priming versus T-cell tolerance. As such, therapeutic induction of inflammatory APCs might override immune tolerance and enhance the efficacy of immunotherapeutic strategies targeting hematologic tumors. Lenalidomide (CC5013) is a thalidomide analogue with immunomodulatory properties. Phase I and Phase II clinical trials in patients with myelodysplastic syndrome (MDS) have shown high frequency of erythropoietic responses, particularly in patients with 5q31 deletion associated with emergence of polyclonal lymphoid infiltrate in responding patient bone marrows. This observation raised the question as to whether immunological mechanism(s) may mediate, at least in part, the beneficial effect of CC5013 in patients with MDS. To gain further insight into the effects of Lenalidomide on APC’s function and regulation of antigen-specific CD4+ T-cell responses, we treated peritoneal elicited macrophages (PEM) and bone marrow-derived dendritic cells (DCs) with escalating concentration of Lenalidomide in vitro. Enhanced expression of both B7.1 and B7.2 co-stimulatory molecules was observed in Lenalidomide-treated APCs relative to untreated APCs. No difference in the expression of MHC class II molecules or CD40 was detected. Assessment of cytokine production by ELISA showed that Lenalidomide-treated APCs produce higher levels of TNF-a, IL-6 and IL-10 in response to LPS stimulation as compared to untreated APCs. Next, we evaluated the ability of Lenalidomide-treated APCs to present cognate antigen to naïve and tolerant CD4+ T-cells specific for a MHC class II restricted epitope of influenza hemagglutinin (HA). We found that treatment of either PEM or DC with low doses of Lenalidomide (range: 1.5–12.5 uM) significantly enhanced their antigen-presenting capabilities leading to effective priming of naïve CD4+ T-cells confirmed by their increased production of IL-2 and IFN-gamma in response to cognate antigen. Taken together, our results shows that by inducing inflammatory APCs, Lenalidomide directs the outcome of antigen-specific T-cell responses. Furthermore, they have broadened the scope of this drug as a promising adjuvant in cancer immunotherapy.


2003 ◽  
Vol 112 (5) ◽  
pp. 854-860 ◽  
Author(s):  
Dagmar von Bubnoff ◽  
Daniel Hanau ◽  
Joerg Wenzel ◽  
Osamu Takikawa ◽  
Brian Hall ◽  
...  

2006 ◽  
Vol 176 (7) ◽  
pp. 4021-4028 ◽  
Author(s):  
Giorgio Raimondi ◽  
Ivan Zanoni ◽  
Stefania Citterio ◽  
Paola Ricciardi-Castagnoli ◽  
Francesca Granucci

10.1038/3488 ◽  
1998 ◽  
Vol 16 (11) ◽  
pp. 1045-1049 ◽  
Author(s):  
Huang-Ge Zhang ◽  
Di Liu ◽  
Yuji Heike ◽  
PingAr Yang ◽  
Zheng Wang ◽  
...  

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2392-2392
Author(s):  
Hongwei Wang ◽  
Fengdong Cheng ◽  
P. Horna ◽  
I.V. Suarez ◽  
Jian Wu ◽  
...  

Abstract Tumor-antigen-specific T-cell tolerance imposes a significant barrier to the development of effective therapeutic cancer vaccines. Bone marrow-derived antigen presenting cells (APCs) are critical in the induction of this unresponsive state. The requirement for APCs in tolerance induction, together with their well-known role in priming T-cell antitumor responses place APCs at the crossroads of immune activation versus immune tolerance and points to manipulation of these cells as an enticing strategy to modulate T-cell responses against tumors. Identification of the intracellular mechanisms by which APCs induces either T-cell outcome represents therefore a critical step to better understand and overcome tumor-induced immune tolerance. Histones tail plays an important role in modulation of gene transcription. Emerging evidence suggest that inhibition of hystone deacetylases (HDAC) increases the expression of inflammatory genes. Given that the inflammatory status of the APC at the time of antigen presentation is central in determining T-cell priming versus T-cell tolerance, we evaluated the effects of the HDAC inhibitor LAQ842 (Novartis Pharmaceutical Inc.) on APC function and regulation of antigen-specific CD4+ T-cell responses. First, treatment of peritoneal elicited macrophages (PEM) or bone marrow derided dendritic cells (DCs) with increasing concentrations of LAQ842 resulted in enhanced acetylation of hystones H-2A, H-2B, H3 and H4. Analysis of the expression of MHC class molecules and co-stimulatory molecules revealed a significant increase in B7.2 and CD40 in LAQ842-treated APCs as compared to untreated APCs. Utilizing multi-template RNA probes and ELISA we found that LAQ842-treated APCs produce enhanced levels of several inflammatory mediators such as IL-1a, IL-1b, IL-6, TNF-a and RANTES relative to untreated APCs. Similarly, in response to LPS-stimulation, LAQ842-treated APCs produce significant higher levels of the pro-inflammatory cytokine IL-12 but reduce production of the anti-inflammatory cytokine IL-10 as determined by RT-PCR and ELISA. Furthermore, by chromatin immune precipitation (CHIP) assays we found that LAQ842-treated APCs display an increased acetylation of histones associated with the IL-12 promoter but a diminished acetylation of histones at the IL-10 promoter in response to LPS stimulation. Next, we evaluated whether the inflammatory APCs induced by LAQ842 were capable of effectively present antigen and prime productive antigen-specific T-cell responses. In vitro treatment of PEM or DCs with increasing concentrations of LAQ842 resulted in an enhanced presentation of HA-peptide to naïve CD4+ T cells specific for a MHC class II restricted epitope of influenza hemagglutinin (HA). Indeed, these clonotypic T cells display an enhanced HA-specific proliferation, IL-2 and IFN-gamma production relative to clonotypic T cells that encountered HA-antigen on untreated APCs. More importantly, LAQ842-treated APCs were able to restore the responsiveness of tolerant CD4+ T-cells isolated from lymphoma bearing hosts. By demonstrating that HDAC inhibitor induces inflammatory APCs capable of restoring the responsiveness of tolerant T-cells, our studies have unveiled a previously unknown immunological effect of these agents and have broadened their clinical scope as promising adjuvants in cancer immunotherapy.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 520-520
Author(s):  
Hongwei Wang ◽  
Zi Wang ◽  
Fengdong Cheng ◽  
Karrune V. Woan ◽  
Jennifer Rock-Klotz ◽  
...  

Abstract Abstract 520 Histones play a critical role in transcriptional regulation, cell cycle progression and developmental events. Histone acetylation/deacetylation alters chromatin structure and affects transcription factor access to DNA. Histone deacetylase inhibitors (HDI) induce growth arrest, cellular differentiation, and apoptosis and are being pursued as anticancer drugs. Interestingly, in addition to their antitumor properties, HDI have also been shown to modulate inflammatory responses. Recently, we have found that HDAC6 is required for the production of the immunosuppressive cytokine IL-10 by APCs. Given the role of this cytokine in T-cell tolerance induction we asked whether inhibition of HDAC6 with Tubastatin A, a potent and selective HDAC6 inhibitor would influence the inflammatory status of APCs and their ability to determine activation versus tolerance of antigen-specific CD4+ T cells in vitro. First, treatment of peritoneal elicited macrophages (PEM) with increasing concentration of Tubastatin A resulted in enhanced tubulin acetylation which was accompanied by enhanced expression of co-stimulatory molecules in treated cells. In addition, Tubastatin-A treated PEM were unable to produce IL-10 and TNF-a in response to LPS stimulation. In sharp contrast, Tubastatin-A treated PEM produce higher level of the pro-inflammatory cytokines IL-12 and IL-6. Next, we evaluated the ability of Tubastatin A-treated APCs to present cognate antigen to naïve and tolerant CD4+ T-cells specific for a MHC class II restricted epitope of influenza hemagglutinin (HA). We found that treatment of PEM with Tubastatin A significantly enhanced their antigen-presenting capabilities leading to effective priming of naïve CD4+ T-cells confirmed by their increased production of IL-2 and IFN-g in response to cognate antigen. More importantly, Tubastatin-A treated APCs were able to restore the responsiveness of tolerant CD4+ T cells isolated from lymphoma bearing mice. Taken together, selective HDAC6 inhibition with Tubastatin A provides a novel therapeutic approach to induce inflammatory APCs and overcome the significant barrier that T-cell tolerance has imposed to effective lymphoma immunotherapy. Disclosures: No relevant conflicts of interest to declare.


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