Combined NKT cell activation and influenza virus vaccination boosts memory CTL generation and protective immunity

Guillonneau, Carole; Mintern, Justine D.; Hubert, François Xavier; Hurt, Aeron C.; Besra, Gurdyal S.; Porcelli, Steven A.; Barr, Ian G.; Doherty, Peter C.; Godfrey, Dale I.; Turner, Stephen J.

doi:10.1073/pnas.0813309106

Cited by 118 publications

(112 citation statements)

References 37 publications

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“…iNKT-cell activation promoted a mucosal IgA response that was not seen in IL-4-deficient mice. Another report confirmed that intranasal vaccination in the presence of a-GalCer induced cross-protection against heterologous virus, which is associated with increased CTL survival and longer-lived memory [59]. Nasal vaccination with co-administration of another iNKTcell agonist, a-C-GalCer, enhanced the IgG response and IFN production by virus-specific CD81T cells, leading to improved survival [60].…”

Section: Antiviral Vaccination Based On Inkt-cell Stimulationsupporting

confidence: 51%

“…Correspondence: Dr. Agnè s Lehuen e-mail: agnes.lehuen@inserm.fr [7,29,30] HSV-2 ds-DNA impaired viral clearance [32] HIV-1 [50,56,[57][58][59][60] surface and retaining it in the trans-Golgi network. This effect depends on a tyrosine-based motif present in the CD1d intracytoplasmic tail that interacts with the viral Nef protein [8,9].…”

Section: Mini-reviewmentioning

confidence: 99%

“…HSV type 1 (HSV-1) infection leads to defective CD1d recycling from the endosome to the cell surface, due to its trapping in the late endosomal compartment and resulting in reduced cell-surface expression [7]. Likewise, HIV type 1 (HIV-1) down-regulates CD1d expression by increasing CD1d internalization from the cell [50,56,[57][58][59][60] Eur. …”

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confidence: 99%

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NKT cells: Friend or foe during viral infections?

Diana

Lehuen

2009

Eur J Immunol

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NKT cells are innate-like T lymphocytes that are found in rodents and primates. They are non-conventional T cells restricted by the CD1d molecule that presents self and exogenous glycolipids. NKT cells are unique in their ability to promptly secrete copious amounts of cytokines such as IFN-c and IL-4. Once activated, NKT cells can provide maturation signals to downstream cells, including DC, NK cells, and lymphocytes, thereby contributing to both innate and acquired immunity. Accordingly, NKT cells can influence a wide array of immune responses, including tumor surveillance, maintenance of self-tolerance and anti-infectious defenses. Studies performed with NKT-cell-deficient mice have shown that these cells are critical for the clearance of various pathogens. During bacterial infections, NKT cells can be activated either indirectly by DC or directly by bacterial lipid antigens presented by CD1d. Although viruses do not contain lipid antigens, NKT cells have also been implicated in antiviral responses. The capacity of NKT cells to regulate viral immune-surveillance, either constitutively or post-activation, makes them an attractive clinical target. In this review, we summarize recent publications dealing with the functions and relevance of NKT cells in the context of viral infections, both in murine models and in humans. (Table 1). Immune evasion by impairing CD1d-mediated antigen presentationSeveral viruses have developed immune-evasion strategies that impair CD1d-mediated antigen presentation, suggesting a role for NKT cells in antiviral responses. Infection by Kaposi sarcomaassociated herpes virus down-regulates cell-surface CD1d expression [6]. This effect is due to two viral modulators of immune recognition proteins, which ubiquitinate the cytoplasmic tail of CD1d and thereby accelerates CD1d endocytosis. HSV type 1 (HSV-1) infection leads to defective CD1d recycling from the endosome to the cell surface, due to its trapping in the late endosomal compartment and resulting in reduced cell-surface expression [7]. Likewise, HIV type 1 (HIV-1) down-regulates CD1d expression by increasing CD1d internalization from the cell [50,56,[57][58][59][60] Eur. Mini-Review

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Section: Antiviral Vaccination Based On Inkt-cell Stimulationsupporting

confidence: 51%

Section: Mini-reviewmentioning

confidence: 99%

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NKT cells: Friend or foe during viral infections?

Diana

Lehuen

2009

Eur J Immunol

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“…IDO inhibitors exacerbated T-cell-mediated pathology in models of tumor growth and autoimmune, infectious, and allergic diseases, and are currently under evaluation as potential tumor vaccine adjuvants in clinical settings (1,2). By analogy to the tumor-protective effects of IDO, some pathogens may exploit IDO to facilitate persistence and IDO may attenuate vaccine-induced immunity (3)(4)(5)(6). Consistent with this paradigm, artificially enhanced IDO activity attenuated graft versus host disease after bone marrow engraftment and prolonged rat lung allograft survival (7)(8)(9).…”

Section: B Cells | T-cell Regulation | Cd19mentioning

confidence: 99%

B-lymphoid cells with attributes of dendritic cells regulate T cells via indoleamine 2,3-dioxygenase

Johnson¹,

Kahler²,

Baban³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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A discrete population of splenocytes with attributes of dendritic cells (DCs) and coexpressing the B-cell marker CD19 is uniquely competent to express the T-cell regulatory enzyme indoleamine 2,3-dioxygenase (IDO) in mice treated with TLR9 ligands (CpGs). Here we show that IDO-competent cells express the B-lineage commitment factor Pax5 and surface immunoglobulins. CD19 ablation abrogated IDO-dependent T-cell suppression by DCs, even though cells with phenotypic attributes matching IDO-competent cells developed normally and expressed IDO in response to interferon γ. Consequently, DCs and regulatory T cells (Tregs) did not acquire T-cell regulatory functions after TLR9 ligation, providing an alternative perspective on the known T-cell regulatory defects of CD19-deficient mice. DCs from B-cell-deficient mice expressed IDO and mediated T-cell suppression after TLR9 ligation, indicating that B-cell attributes were not essential for B-lymphoid IDO-competent cells to regulate T cells. Thus, IDO-competent cells constitute a distinctive B-lymphoid cell type with quintessential T-cell regulatory attributes and phenotypic features of both B cells and DCs. B cells | T-cell regulation | CD19I ndoleamine 2,3-dioxygenase (IDO) is an intracellular enzyme expressed in response to interferons (IFNs) at sites of inflammation. IDO inhibitors exacerbated T-cell-mediated pathology in models of tumor growth and autoimmune, infectious, and allergic diseases, and are currently under evaluation as potential tumor vaccine adjuvants in clinical settings (1, 2). By analogy to the tumor-protective effects of IDO, some pathogens may exploit IDO to facilitate persistence and IDO may attenuate vaccine-induced immunity (3-6). Consistent with this paradigm, artificially enhanced IDO activity attenuated graft versus host disease after bone marrow engraftment and prolonged rat lung allograft survival (7-9). Thus, IDO-dependent T-cell regulation occurs in multiple settings of chronic inflammation relevant to clinical syndromes.Despite the potential benefits of manipulating IDO activity to improve therapy in chronic inflammatory syndromes, little is known about the cellular basis of IDO-mediated T-cell regulation in physiologic settings. Antigen presenting cells (APCs) expressing IDO, such as dendritic cells (DCs), activate regulatory T cells (Tregs) and directly suppress effector T cells at sites of tissue inflammation (10, 11). Cells with functional and phenotypic attributes of DCs in mice and humans are competent to express IDO and regulate T-cell responses (11-15). In mice, splenocytes uniquely competent to mediate T-cell suppression via IDO after in vivo treatment with TLR9 ligands (CpGs) were a rare cell type located in splenic red pulp with phenotypic attributes of DCs (CD11c, CD8α, CD80/86, MHCII). IDO-competent cells also expressed B220 and the B-cell lineage marker CD19, but not the plasmacytoid DC (pDC) marker PDCA/120G8 (13). After CTLA4-Ig and CpG treatment, IDO-competent cells produced IFNα (15, 16), a functional attribute of pDCs and ...

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“…Cells were stained with Abs against CD8, and the percentages of IFN-g-and TNF-asecreting cells among total CD8 + T cells were measured by flow cytometry (23).…”

Section: Intracellular Cytokine-staining Assaymentioning

confidence: 99%

Rapid Deletion and Inactivation of CTLs upon Recognition of a Number of Target Cells over a Critical Threshold

Prato

Zhan

Mintern

et al. 2013

The Journal of Immunology

Self Cite

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Initiation of CTL responses against foreign pathogens also primes anti-self CTLs. Mechanisms of CTL inactivation inhibit anti-self CTLs to prevent tissue damage. These mechanisms are exploited by pathogens and tumors to evade the immune response, and present a major hurdle to adoptive CTL therapies. It is unclear whether CTL inactivation is Ag specific and, if so, which APCs are involved. Potential candidates include the target cells themselves, dendritic cells, myeloid-derived suppressor cells, and macrophages. In this study, we show that lymphoma-specific CTLs are rapidly deleted in an Ag-specific manner after adoptive transfer into lymphoma-bearing mice, and the surviving CTLs are functionally impaired. The only APCs responsible were the target cells directly presenting Ag, notwithstanding the presence of myeloid-derived suppressor cells, and CD8+ dendritic cells cross-presenting tumor Ag. The capacity to inactivate CTLs critically depended on the number of tumor/target cells; small numbers of targets were readily killed, but a large number caused quick deletion and functional inactivation of the CTLs. Application of mild, noninflammatory, and nonlymphoablative chemotherapy to specifically reduce tumor burden before CTL injection prevented CTL deletion and inactivation and allowed eradication of tumor. Our results advocate the use of adoptive CTL therapy soon after mild chemotherapy. They also suggest a simple mechanism for Ag-specific impairment of anti-self CTLs in the face of an active anti-foreign CTL response.

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Combined NKT cell activation and influenza virus vaccination boosts memory CTL generation and protective immunity

Cited by 118 publications

References 37 publications

NKT cells: Friend or foe during viral infections?

NKT cells: Friend or foe during viral infections?

B-lymphoid cells with attributes of dendritic cells regulate T cells via indoleamine 2,3-dioxygenase

Rapid Deletion and Inactivation of CTLs upon Recognition of a Number of Target Cells over a Critical Threshold

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