Killer T cells regulate antigen presentation for early expansion of memory, but not naive, CD8+ T cell.
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ABSTRACT:
SUBMITTER: Belz GT
PROVIDER: S-EPMC1840050 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cytokine-induced killer cells (CIK) have been used in clinic for adoptive immunotherapy in a variety of malignant tumors and have improved the prognosis of cancer patients. However, there are individual differences in the CIK cell preparations including the obvious differences in the ratio of effector CIK cells among different cancer patients. Infusion of such heterogeneous immune cell preparation is an important factor that would affect the therapeutic efficacy. We report here the enrichment and expansion of CD8+ cells from CIK cells cultured for one week using magnetic activated cell sorting (MACS). These enriched CD8+ CIK cells expressed T cell marker CD3 and antigen recognition receptor NKG2D. Phenotypic analysis showed that CD8+ CIK cells contained 32.4% of CD3+ CD56+ natural killer (NK)-like T cells, 23.6% of CD45RO+ CD28+, and 50.5% of CD45RA+ CD27+ memory T cells. In vitro cytotoxic activity assay demonstrated that the enriched CD8+ CIK cells had significant cytotoxic activity against K562 cells and five ovarian cancer cell lines. Intriguingly, CD8+ CIK cells had strong cytotoxic activity against OVCAR3 cells that has weak binding capability to NKG2D. Flow cytometry and quantitative RT-PCR analysis revealed that OVCAR3 cells expressed HLA-I and OCT4 and Sox2, suggesting that CD8+ CIK cells recognize surface antigen via specific T cell receptor and effectively kill the target cells. The results suggest that transplantation of such in vitro enriched and expanded OCT4-specific CD8+ CIK cells may improve the specific immune defense mechanism against cancer stem cells, providing a novel avenue of cancer stem cell targeted immunotherapy for clinical treatment of ovarian cancer.
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Project description:Various populations of memory phenotype CD8(+) T cells have been described over the last 15-20 y, all of which possess elevated effector functions relative to naive phenotype cells. Using a technique for isolating Ag-specific cells from unprimed hosts, we recently identified a new subset of cells, specific for nominal Ag, but phenotypically and functionally similar to memory cells arising as a result of homeostatic proliferation. We show in this study that these virtual memory (VM) cells are independent of previously identified innate memory cells, arising as a result of their response to IL-15 trans presentation by lymphoid tissue-resident CD8α(+) dendritic cells in the periphery. The absence of IL-15, CD8(+) T cell expression of either CD122 or eomesodermin or of CD8a(+) dendritic cells all lead to the loss of VM cells in the host. Our results show that CD8(+) T cell homeostatic expansion is an active process within the nonlymphopenic environment, is mediated by IL-15, and produces Ag-inexperienced memory cells that retain the capacity to respond to nominal Ag with memory-like function. Preferential engagement of these VM T cells into a vaccine response could dramatically enhance the rate by which immune protection develops.
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Project description:CD8+ T cells play a critical role in adaptive immunity, differentiating into CD8+ memory T cells that form the basis of protective cellular immunity. Vaccine efficacy is attributed to long-term protective immunity, and understanding the parameters that regulate development of CD8+ T cells is critical to the design of T cell-mediated vaccines. We show in this study using mouse models that two distinct parameters, TCR signal strength (regulated by the tyrosine kinase ITK) and Ag affinity, play important but separate roles in modulating the development of memory CD8+ T cells. Unexpectedly, our data reveal that reducing TCR signal strength along with reducing Ag affinity for the TCR leads to enhanced and accelerated development of CD8+ memory T cells. Additionally, TCR signal strength is able to regulate CD8+ T cell effector cytokine R production independent of TCR Ag affinity. Analysis of RNA-sequencing data reveals that genes for inflammatory cytokines/cytokine receptors are significantly altered upon changes in Ag affinity and TCR signal strength. Furthermore, our findings show that the inflammatory milieu is critical in regulating this TCR signal strength-mediated increase in memory development, as both CpG oligonucleotide treatment or cotransfer of wild-type and Itk-/- T cells eliminates the observed increase in memory cell formation. These findings suggest that TCR signal strength and Ag affinity independently contribute to CD8+ memory T cell development, which is modulated by inflammation, and suggest that manipulating TCR signal strength along with Ag affinity, may be used to tune the development of CD8+ memory T cells during vaccine development.
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Project description:The commitment of naive CD8 T cells to effector or memory cell fates can occur after a single day of antigenic stimulation even though virus-derived antigens (Ags) are still presented by DCs long after acute infection is resolved. However, the effects of extended Ag presentation on CD8 T cells are undefined and the mechanisms that regulate prolonged Ag presentation are unknown. We showed that the sustained presentation of two different epitopes from influenza virus by DCs prevented the premature contraction of the primary virus-specific CD8 T cell response. Although prolonged Ag presentation did not alter the number of memory CD8 T cells that developed, it was essential for programming the capacity of these cells to proliferate, produce cytokines, and protect the host after secondary challenge. Importantly, prolonged Ag presentation by DCs was dependent on virus-specific, isotype-switched antibodies (Abs) that facilitated the capture and cross-presentation of viral Ags by FcγR-expressing DCs. Collectively, our results demonstrate that B cells and Abs can regulate the quality and functionality of a subset of antiviral CD8 T cell memory responses and do so by promoting sustained Ag presentation by DCs during the contraction phase of the primary T cell response.
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Project description:BackgroundThe identification of the signals that should be provided by antigen-presenting cells (APCs) to induce a CD8(+) T cell response in vivo is essential to improve vaccination strategies using antigen-loaded APCs. Although dendritic cells have been extensively studied, the ability of other APC types, such as B cells, to induce a CD8(+) T cell response have not been thoroughly evaluated.Methodology/principal findingsIn this manuscript, we have characterized the ability of CD40-activated B cells, stimulated or not with Toll-like receptor (TLR) agonists (CpG or lipopolysaccharide) to induce the response of mouse naïve CD8(+) T cells in vivo. Our results show that CD40-activated B cells can directly present antigen to naïve CD8(+) T cells to induce the generation of potent effectors able to secrete cytokines, kill target cells and control a Listeria monocytogenes infection. However, CD40-activated B cell immunization did not lead to the proper formation of CD8(+) memory T cells and further maturation of CD40-activated B cells with TLR agonists did not promote the development of CD8(+) memory T cells. Our results also suggest that inefficient generation of CD8(+) memory T cells with CD40-activated B cell immunization is a consequence of reduced Bcl-6 expression by effectors and enhanced contraction of the CD8(+) T cell response.ConclusionsUnderstanding why CD40-activated B cell immunization is defective for the generation of memory T cells and gaining new insights about signals that should be provided by APCs are key steps before translating the use of CD40-B cell for therapeutic vaccination.
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Project description:Memory CD8(+) T cells are programmed during the primary response for robust secondary responsiveness. Here we show that CD8(+) T cells responding to different epitopes of influenza virus received qualitatively different signals during the primary response that altered their secondary responsiveness. Nucleoprotein (NP)-specific CD8(+) T cells encountered antigen on CD40-licensed, CD70-expressing, CD103(-)CD11b(hi) dendritic cells (DCs) at later times in the primary response. As a consequence, they maintained CD25 expression and responded to interleukin-2 (IL-2) and CD27, which together programmed their robust secondary proliferative capacity and interferon-γ (IFN-γ)-producing ability. In contrast, polymerase (PA)-specific CD8(+) T cells did not encounter antigen-bearing, CD40-activated DCs at later times in the primary response, did not receive CD27 and CD25 signals, and were not programmed to become memory CD8(+) T cells with strong proliferative and cytokine-producing ability. As a result, CD8(+) T cells responding to abundant antigens, like NP, dominated the secondary response.
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Project description:microRNAs have recently emerged as master regulators of gene expression during development and cell differentiation. Although profound changes in gene expression also occur during antigen-induced T cell differentiation, the role of miRNAs in the process is not known. We compared the miRNA expression profiles between antigen-specific naïve, effector and memory CD8+ T cells using 3 different methods--small RNA cloning, miRNA microarray analysis and real-time PCR. Although many miRNAs were expressed in all the T cell subsets, the frequency of 7 miRNAs (miR-16, miR-21, miR-142-3p, miR-142-5p, miR-150, miR-15b and let-7f) alone accounted for approximately 60% of all miRNAs, and their expression was several fold higher than the other expressed miRNAs. Global downregulation of miRNAs (including 6/7 dominantly expressed miRNAs) was observed in effector T cells compared to naïve cells and the miRNA expression levels tended to come back up in memory T cells. However, a few miRNAs, notably miR-21 were higher in effector and memory T cells compared to naïve T cells. These results suggest that concomitant with profound changes in gene expression, miRNA profile also changes dynamically during T cell differentiation. Sequence analysis of the cloned mature miRNAs revealed an extensive degree of end polymorphism. While 3'end polymorphisms dominated, heterogeneity at both ends, resembling drosha/dicer processing shift was also seen in miR-142, suggesting a possible novel mechanism to generate new miRNA and/or to diversify miRNA target selection. Overall, our results suggest that dynamic changes in the expression of miRNAs may be important for the regulation of gene expression during antigen-induced T cell differentiation. Our study also suggests possible novel mechanisms for miRNA biogenesis and function.
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Project description:The induction of long-lived effector CD8+ T cells is key to the development of efficient cancer vaccines. In this study, we demonstrated that a Toll-like receptor 2 (TLR2) agonist-fused antigen increased antigen presentation via TLR2 signaling and induced effector memory-like CD8+ T cells against cancer after immunization. The N-terminus of ovalbumin (OVA) was biologically fused with a bacterial lipid moiety TLR2 agonist to produce a recombinant lipidated ovalbumin (rlipo-OVA). We demonstrated that rlipo-OVA activated bone marrow-derived dendritic cells (BM-DCs) maturation and increased antigen presentation by major histocompatibility complex (MHC) class I via TLR2. After immunization, rlipo-OVA skewed the immune response towards T helper (Th) 1 and induced OVA-specific cytotoxic T lymphocyte (CTL) responses. Moreover, immunization with rlipo-OVA induced higher numbers of effector memory (CD44+CD62L-) CD8+ T cells compared with recombinant ovalbumin (rOVA) alone or rOVA mixed with the TLR2 agonist Pam3CSK4. Accordingly, the CD27+CD43+ effector memory CD8+ T cells expressed high levels of the long-lived CD127 marker. The administration of rlipo-OVA could inhibit tumor growth, but the anti-tumor effects were lost after the depletion of CD8 or CD127 cells in vivo. These findings suggested that the TLR2 agonist-fused antigen induced long-lived memory CD8+ T cells for efficient cancer therapy.
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