Costimulation of CD8 T Cell Responses by OX40

Bansal-Pakala, Pratima; Halteman, Beth S.; Cheng, Mary; Croft, Michael

doi:10.4049/jimmunol.172.8.4821

Cited by 163 publications

(165 citation statements)

References 36 publications

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“…In our studies we demonstrate that OX40L contributes to the enhancement of antigen-dependent IFN-c production by CpG-stimulated PDC both in NKT cells and CD8 T cells. Our data extend earlier studies in the literature in which OX40-mediated costimulation was found to regulate the accumulation of antigen-stimulated CD8 cells [61]. Of note, in our studies the Th1 cytokine IFN-a was required (but not sufficient) for the PDC-mediated enhanced IFNc production in NKT cells.…”

Section: Discussionsupporting

confidence: 90%

CpG ODN enhance antigen-specific NKT cell activation via plasmacytoid dendritic cells

et al. 2005

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Human Va24 + Vb11 + natural killer T cells (NKT cells) are "natural memory" T cells that detect glycolipid antigens such as a-galactosylceramide (a-GalCer) presented on CD1d.In the present study we found that highly purified Va24 + NKT cells lack TLR9 mRNA, and thus are not sensitive towards stimulation with CpG oligodeoxynucleotides (ODN). Within PBMC, however, CpG ODN synergistically activated NKT cells stimulated with their cognate antigen a-GalCer. Depletion of plasmacytoid dendritic cells (PDC) or myeloid dendritic cells (MDC) revealed that both DC subsets were necessary for the synergistic activation of NKT cells by a-GalCer and CpG ODN. While PDC were responsible for the stimulation of NKT cells with CpG ODN, MDC but not PDC presented a-GalCer via CD1d. Partial activation of NKT cells was mediated by PDC-derived IFN-a, whereas full activation of NKT cells as indicated by IFN-c production required cell-tocell contact of PDC and NKT cells in addition to IFN-a; OX40 was involved in this interaction. We conclude that CpG-activated PDC enhance a-GalCer-specific NKT cell activation, and bias activated NKT cells towards a Th1 phenotype. Our results lead to a novel concept of PDC function: to regulate effector activity of antigen-stimulated T cells in a cell contact-dependent manner without the need of simultaneous presentation of the cognate T cell antigen. IntroductionNatural killer T (NKT) cells represent a small subset of non-conventional innate T cells with a restricted TCR repertoire for the recognition of glycolipid antigens presented on CD1d, an MHC class I-like molecule. NKT cells express markers of NK cells and exhibit an activated memory phenotype. Depending on the microenvironment and the type of stimulation, they can release large amounts of both Th1 and Th2 cytokines (especially IL-4 and IFN-c) and show cytotoxic activity in vitro (reviewed in [1][2][3]). In both mice and man NKT cells express a homologous semi-invariant TCR that in humans consists of a Va24 chain preferentially paired with a Vb11 chain [4]. In mice, NKT cells are most frequent in the liver (about 30% of hepatic T cells), bone marrow and thymus (reviewed in [5]). Smaller NKT cell populations are present in spleen and blood (reviewed in [5]). Similar to their murine counterparts, human NKT cells preferen-A. M., S. R. and V. H. equally contributed to this manuscript. tially accumulate in the liver though with a far lower frequency than in mice (4% of hepatic T cells) ([6, 7] and reviewed in [1,5]). Due to the conserved TCR, both mouse and human NKT cells recognise the same specific glycolipid antigen a-galactosylceramide (a-GalCer) when presented by CD1d molecules on antigen-presenting cells (APC) [8][9][10]. Originally isolated from a marine sponge, aGalCer was first described as an agent with strong antimetastatic activity in mice and later found to specifically activate NKT cells in a CD1d-restricted manner [8,11,12]. Glycolipid antigens similar to a-GalCer have been detected in certain bacteria and under some abnormal conditions...

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Section: Discussionsupporting

confidence: 90%

CpG ODN enhance antigen-specific NKT cell activation via plasmacytoid dendritic cells

et al. 2005

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“…The function of this co-stimulatory receptor has mostly been studied in CD4 T cells, but has also been shown to enhance CD8 T cell responses [43,44]. As OX40 ligand is expressed by B cells, the CXCR5 + CD8 T cells could be positively regulated by B cells in the follicle via this receptor pair [45].…”

Section: Discussionmentioning

confidence: 99%

CXCR5⁺ CCR7^– CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles

et al. 2007

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Naive and central memory CD8 T cells use CCR7 to recirculate through T cell zones of secondary lymphoid organs where they can encounter antigen. Here we describe a subset of human CD8 T cells expressing CXCR5 which enables homing in response to CXCL13 produced within B cell follicles. CXCR5 + CD8 T cells were found in tonsil B cell follicles, and isolated cells migrated towards CXCL13 in vitro. They expressed CD27, CD28, CD45RO, CD69, and were CD7 low , and produced IFN-c and granzyme A but lacked perforin, a functional profile suggesting that these cells are early effector memory cells in the context of contemporary T cell differentiation models. Receptors important in the interaction with B cells, including CD70, OX40 and ICOS, were induced upon activation, and CXCR5 + CD8 T cells could to some extent support survival and IgG production in tonsil B cells. Furthermore, CXCR5 + CD8 T cells expressed CCR5 but no CCR7, suggesting a migration pattern distinct from that of follicular CD4 T cells. The finding that a subset of early effector memory CD8 T cells use CXCR5 to locate to B cell follicles indicates that MHC class I-restricted CD8 T cells are part of the follicular T cell population. IntroductionCD8 T cells are lymphocytes of the adaptive immune system which recognize viral and bacterial peptides presented by MHC class I molecules and are indispensable in the control of many intracellular infections [1]. When appropriately stimulated by antigen presented by dendritic cells (DC) in secondary lymphoid tissues, they proliferate vigorously, become effector cells, and upon resolution of infection a small population of antigen-specific CD8 T cells are maintained as long-lived memory cells [2][3][4]. A primary effector mechanism of CD8 T cells is the killing of infected cells via the targeted release of the lytic effector molecules perforin and granzymes, and via expression of death receptors. However, there is significant functional heterogeneity in CD8 T cells and they are also efficient in producing anti-viral and pro-inflammatory cytokines [5][6][7][8]. The effector mechanisms used may depend on the pathogen and on the type of cell or tissue that is infected [8].CD8 T cell responses involve the differentiation of naive T cells into distinct types of effector and memory cells [2, 3,9]. One approach to analyse a T cell response is to examine the expression of receptors that mediate homing of T cells, such as CD62L, which binds to glycosylation-dependent cell adhesion molecule 1 on [4,20,21]. CXCR5 is a chemokine receptor which is expressed on all B cells and on specialized subsets of DC and T cells [22]. It has only one known ligand, the chemokine CXCL13, mainly produced by stromal cells and follicular DC within B cell follicles [23][24][25]. CXCR5 + CD4 T cells, known as follicular homing T helper cells, are found in B cell follicles and contribute to the generation of effective humoral immune responses by supporting antibody production and isotype class switching [26,27]. However, some of the processes and mec...

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“…Importantly, both receptors are expressed on CD8 1 T cells following TCR signalling and appear to have similar roles in activation [31] with agonistic mAb directly enhancing CD8 1 T-cell responses, largely through improved survival of antigen-activated T cells [30,41]. Both 4-1BB and OX40 interact with common TRAF proteins, activate NFkB pathways and induce expression of anti-apoptotic Bcl-2 family molecules [42][43][44].…”

Section: Discussionmentioning

confidence: 99%

Optimising anti‐tumour CD8 T‐cell responses using combinations of immunomodulatory antibodies

et al. 2008

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Immunostimulatory mAb as vaccine adjuvants for the treatment of cancer hold considerable potential for boosting weak responses when used against immunogenic tumours, or in combination with various other vaccines. We now show that when administered with OVA, the combination of anti-4-1BB mAb with anti-CD40, anti-OX40 or anti-CD25 resulted in a fourfold enhancement in the antigen-specific T-cell response compared with anti-4-1BB mAb alone, with a similar enhancement in memory responses following rechallenge with OVA. Although the number of antigen-specific T-cells generated after treatment with each of the combinations was similar, marked functional differences were detected. In particular, anti-4-1BB/anti-CD25 resulted in excellent expansion of specific CD81 T cells but produced fewer IFN-c-secreting effector cells than the other combinations. Anti-4-1BB/anti-OX40 proved to be the most potent, inducing the most effective T-cell responses in the RIPmOVA diabetes model with adoptively transferred OVA-specific T cells, and, when given with a peptide vaccine, protecting mice against the poorly immunogenic B16-F10 tumour. Overall the results suggest that although these combinations of mAb look promising in terms of their therapeutic potential, further functional assays are needed to compare their effects.

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Costimulation of CD8 T Cell Responses by OX40

Cited by 163 publications

References 36 publications

CpG ODN enhance antigen-specific NKT cell activation via plasmacytoid dendritic cells

CpG ODN enhance antigen-specific NKT cell activation via plasmacytoid dendritic cells

CXCR5⁺ CCR7^– CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles

Optimising anti‐tumour CD8 T‐cell responses using combinations of immunomodulatory antibodies

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Costimulation of CD8 T Cell Responses by OX40

Cited by 163 publications

References 36 publications

CpG ODN enhance antigen-specific NKT cell activation via plasmacytoid dendritic cells

CpG ODN enhance antigen-specific NKT cell activation via plasmacytoid dendritic cells

CXCR5+ CCR7– CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles

Optimising anti‐tumour CD8 T‐cell responses using combinations of immunomodulatory antibodies

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CXCR5⁺ CCR7^– CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles