Concomitant Helper Response Rescues Otherwise Low Avidity CD8+ Memory CTLs to Become Efficient Effectors In Vivo

Kumaraguru, Udayasankar; Suvas, Susmit; Biswas, Partha S.; Azkur, Ahmet Kürşat; Rouse, Barry T.

doi:10.4049/jimmunol.172.6.3719

Cited by 26 publications

(17 citation statements)

References 30 publications

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“…IL-12 enhances Th1 cell polarization, leading to more IFNγ and TNFα production. Through these cytokines, Th1 cells synergize with CTL and DC in anti-tumor immunity [4][5][6][7][8][9]. We have shown previously that immunization with attenuated activated autologous T cells leads to more IL-12 production.…”

Section: Discussionmentioning

confidence: 99%

“…Many reports have shown that activity of Th1 cells is downregulated in patients with malignant tumors. For example, tumor patients had lower concentrations of Th1 cytokines in serum, which may lead to low CTLmediated anti-tumor activity and dampened DC function [9][10][11]. Treating patients with IL-2 plus IFNγ may induce tumor regression [12,13].…”

Section: Introductionmentioning

confidence: 99%

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Downregulation of CD4+CD25+ regulatory T cells may underlie enhanced Th1 immunity caused by immunization with activated autologous T cells

Cao

Wang

et al. 2007

Cell Res

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Regulatory T cells (Treg) play important roles in immune system homeostasis, and may also be involved in tumor immunotolerance by suppressing Th1 immune response which is involved in anti-tumor immunity. We have previously reported that immunization with attenuated activated autologous T cells leads to enhanced anti-tumor immunity and upregulated Th1 responses in vivo. However, the underlying molecular mechanisms are not well understood. Here we show that Treg function was significantly downregulated in mice that received immunization of attenuated activated autologous T cells. We found that Foxp3 expression decreased in CD4+CD25+ T cells from the immunized mice. Moreover, CD4+CD25+Foxp3+ Treg obtained from immunized mice exhibited diminished immunosuppression ability compared to those from naïve mice. Further analysis showed that the serum of immunized mice contains a high level of anti-CD25 antibody (about 30 ng/ml, p<0.01 vs controls). Consistent with a role of anti-CD25 response in the downregulation of Treg, adoptive transfer of serum from immunized mice to naïve mice led to a significant decrease in Treg population and function in recipient mice. The triggering of anti-CD25 response in immunized mice can be explained by the fact that CD25 was induced to a high level in the ConA activated autologous T cells used for immunization. Our results demonstrate for the first time that immunization with attenuated activated autologous T cells evokes anti-CD25 antibody production, which leads to impeded CD4+CD25+Foxp3+ Treg expansion and function in vivo. We suggest that dampened Treg function likely contributes to enhanced Th1 response in immunized mice and is at least part of the mechanism underlying the boosted anti-tumor immunity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Downregulation of CD4+CD25+ regulatory T cells may underlie enhanced Th1 immunity caused by immunization with activated autologous T cells

Cao

Wang

et al. 2007

Cell Res

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“…In vivo cytolytic activity was determined as described previously (18). Briefly, splenocytes from C57BL/6 mice were stained with PKH26 (PKH26-GL; Sigma-Aldrich) or 1.5, 0.15, or 0.03 M CFSE.…”

Section: In Vivo Cytotoxicity Assaymentioning

confidence: 99%

“…To evaluate the functional avidities of the effector populations further, we performed an in vivo CTL assay (18). Differentially CFSE-labeled splenocytes from naive syngeneic mice were pulsed with varying concentrations of SIINFEKL peptide (100, 10, or 1 nM) and i.v.…”

Section: Effector T Cells Induced By Pdom-sl8 Vaccination Are Functiomentioning

confidence: 99%

Prolonged Antigen Expression following DNA Vaccination Impairs Effector CD8+ T Cell Function and Memory Development

Radcliffe

Roddick

Stevenson

et al. 2007

The Journal of Immunology

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After priming, naive T cells undergo a program of expansion, contraction, and memory formation. Numerous studies have indicated that only a brief period of antigenic stimulation is required to fully commit CD8+ T cells to this program. Nonetheless, the persistence of Ag may modulate the eventual fate of CD8+ T cells. Using DNA delivery, we showed previously that direct presentation primes high levels of effector CD8+ T cells as compared with cross-presentation. One explanation now revealed is that prolonged cross-presentation limits effector cell expansion and function. To analyze this, we used a drug-responsive system to regulate Ag expression after DNA injection. Reducing expression to a single burst expanded greater numbers of peptide-specific effector CD8+ T cells than sustained Ag. Consequences for memory development were assessed after boosting and showed that, although persistent Ag maintained higher numbers of tetramer-positive CD8+ T cells, these expanded less (∼4-fold) than those induced by transient Ag expression (∼35-fold). Transient expression at priming therefore led to a net higher secondary response. In terms of vaccine design, we propose that the most effective DNA-based CD8+ T cell vaccines will be those that deliver a short burst of Ag.

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“…27 It is now firmly established that for robust and persistent CD8 þ T-cell responses a concomitant CD4 þ T-helper response is needed. [28][29][30][31] Therefore, HLA class II presented tumor-specific epitopes are preferably incorporated in peptide vaccines to promote the CTL-mediated tumor destruction.…”

Section: Vaccination Strategies With Defined T-cell Epitope Containinmentioning

confidence: 99%

Identification of T-cell epitopes for cancer immunotherapy

2007

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The effectiveness of T-cell-mediated immunotherapy of cancer depends on both an optimal immunostimulatory context of the therapy and the proper selection with respect to quality and quantity of the targeted tumor-associated antigens (TAA), and, more precisely, the T-cell epitopes contained in these tumor proteins. Our progressing insight in human leukocyte antigen (HLA) class I and class II antigen processing and presentation mechanisms has improved the prediction by reverse immunology of novel cytotoxic T lymphocyte and T-helper cell epitopes within known antigens. Computer algorithms that in silico predict HLA class I and class II binding, proteasome cleavage patterns and transporter associated with antigen processing translocation are now available to expedite epitope identification. The advent of genomics allows a high-throughput screening for tumor-specific transcripts and mutations, with that identifying novel shared and unique TAA. The increasing power of mass spectrometry and proteomics will lead to the direct identification from the tumor cell surface of numerous novel tumor-specific HLA class I and class II presented ligands. Together, the expanded repertoire of tumor-specific T-cell epitopes will enable more precise immunomonitoring and the development of effective epitope-defined adoptive T-cell transfer and multi-epitope-based vaccination strategies targeting epitopes derived from a wider diversity of TAA presented in a broader array of HLA molecules.

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Concomitant Helper Response Rescues Otherwise Low Avidity CD8+ Memory CTLs to Become Efficient Effectors In Vivo

Cited by 26 publications

References 30 publications

Downregulation of CD4+CD25+ regulatory T cells may underlie enhanced Th1 immunity caused by immunization with activated autologous T cells

Downregulation of CD4+CD25+ regulatory T cells may underlie enhanced Th1 immunity caused by immunization with activated autologous T cells

Prolonged Antigen Expression following DNA Vaccination Impairs Effector CD8+ T Cell Function and Memory Development

Identification of T-cell epitopes for cancer immunotherapy

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