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S Brian Wilson

Publications and source records attributed to S Brian Wilson.

18 recordsLinked to original sources
PubMed2006

CD38 is required for the peripheral survival of immunotolerogenic CD4+ invariant NK T cells in nonobese diabetic mice.

T cell-mediated autoimmune type-1 diabetes (T1D) in NOD mice partly results from this strain's numerical and functional defects in invariant NK T (iNKT) cells. T1D is inhibited in NOD mice treated with the iNKT cell superagonist alpha-galactosylceramide through a process involving enhanced accumulation of immunotolerogenic dendritic cells in pancreatic lymph nodes. Conversely, T1D is accelerated in NOD mice lacking CD38 molecules that play a role in dendritic cell migration to inflamed tissues. Unlike in standard NOD mice, alpha-galactosylceramide pretreatment did not protect the CD38-deficient stock from T1D induced by an adoptively transferred pancreatic beta cell-autoreactive CD8 T cell clone (AI4). We found that in the absence of CD38, ADP-ribosyltransferase 2 preferentially activates apoptotic deletion of peripheral iNKT cells, especially the CD4+ subset. Therefore, this study documents a previously unrecognized role for CD38 in maintaining survival of an iNKT cell subset that preferentially contributes to the maintenance of immunological tolerance.

ADP Ribose Transferases↗
PubMed2006

Activation of plasmacytoid dendritic cells with TLR9 agonists initiates invariant NKT cell-mediated cross-talk with myeloid dendritic cells.

CD1d-restricted invariant NK T (iNKT) cells and dendritic cells (DCs) have been shown to play crucial roles in various types of immune responses, including TLR9-dependent antiviral responses initiated by plasmacytoid DCs (pDCs). However, the mechanism by which this occurs is enigmatic because TLRs are absent in iNKT cells and human pDCs do not express CD1d. To explore this process, pDCs were activated with CpG oligodeoxyribonucleotides, which stimulated the secretion of several cytokines such as type I and TNF-alpha. These cytokines and other soluble factors potently induced the expression of activation markers on iNKT cells, selectively enhanced double-negative iNKT cell survival, but did not induce their expansion or production of cytokines. Notably, pDC-derived factors licensed iNKT cells to respond to myeloid DCs: an important downstream cellular target of iNKT cell effector function and a critical contributor to the initiation of adaptive immune responses. This interaction supports the notion that iNKT cells can mediate cross-talk between DC subsets known to express mutually exclusive TLR and cytokine profiles.

Adult↗
PubMed2005

Impaired cell surface expression of human CD1d by the formation of an HIV-1 Nef/CD1d complex.

The HIV-1 Nef protein causes a decrease in major histocompatibility complex (MHC) class I and CD4 molecule expression on the cell surface. To determine if Nef can affect components of the innate immune response, we assessed the ability of Nef to alter the cell surface expression of human CD1d. In cells co-expressing CD1d and Nef, a substantial reduction in the cell surface level of CD1d was observed, with a concomitant reduction in the activation of CD1d-restricted NKT cells. Nef had a minimal effect on the cell surface expression of a mutant CD1d molecule in which the last 6 or 10 amino acids of the cytoplasmic tail were deleted. Additionally, it was found that Nef physically interacted with wild-type (but not tail-deleted) CD1d. Therefore, one means by which HIV-1 may be able to establish a foothold in an infected individual is by directly interfering with the functional cell surface expression of CD1d.

Antigens, CD1↗
PubMed2005

Activated NKT cells inhibit autoimmune diabetes through tolerogenic recruitment of dendritic cells to pancreatic lymph nodes.

NKT cell activation by alpha-galactosylceramide (alpha-GalCer) inhibits autoimmune diabetes in NOD mice, in part by inducing recruitment to pancreatic lymph nodes (PLNs) of mature dendritic cells (DCs) with disease-protective effects. However, how activated NKT cells promote DC maturation, and what downstream effect this has on diabetogenic T cells was unknown. Activated NKT cells were found to produce a soluble factor(s) inducing DC maturation. Initially, there was a preferential accumulation of mature DCs in the PLNs of alpha-GalCer-treated NOD mice, followed by a substantial increase in T cells. Adoptive transfer of a diabetogenic CD8 T cell population (AI4) induced a high rate of disease (75%) in PBS-treated NOD recipients, but not in those pretreated with alpha-GalCer (8%). Significantly, more AI4 T cells accumulated in PLNs of alpha-GalCer than PBS-treated recipients, while no differences were found in mesenteric lymph nodes from each group. Compared with those in mesenteric lymph nodes, AI4 T cells entering PLNs underwent greater levels of apoptosis, and the survivors became functionally anergic. NKT cell activation enhanced this process. Hence, activated NKT cells elicit diabetes protection in NOD mice by producing a soluble factor(s) that induces DC maturation and accumulation in PLNs, where they subsequently recruit and tolerize pathogenic T cells.

Adjuvants, Immunologic↗
PubMed2005

CD1d and CD1d-restricted iNKT-cells play a pivotal role in contact hypersensitivity.

CD1d-restricted T-cells are activated by glycolipids presented by the major histocompatibility complex class-Ib molecule CD1d, found on the surface of antigen-presenting cells (APC). This interaction between APC, most notably dendritic cells (DC), and CD1d-restricted T-cells is an important regulatory step in the initiation of adaptive immune responses. It is well known that DC play a crucial role in the induction of contact hypersensitivity (CHS), a frequently studied form of in vivo T-cell-mediated immunity. In this study, we show that CD1d-restricted T-cells are also necessary for CHS, because both wild-type mice treated systemically or topically with CD1d glycolipid antagonists and CD1d-restricted T-cell-null mice have markedly diminished CHS responses. Thus, pharmacologic antagonists of CD1d can be used as effective inhibitors of CHS, a prototype for a variety of delayed-type tissue hypersensitivity responses.

Administration, Topical↗
PubMed2004

Natural killer T cells infiltrate neuroblastomas expressing the chemokine CCL2.

CD1d-restricted Valpha24-Jalpha18-invariant natural killer T cells (iNKTs) are potentially important in tumor immunity. However, little is known about their localization to tumors. We analyzed 98 untreated primary neuroblastomas from patients with metastatic disease (stage 4) for tumor-infiltrating iNKTs using TaqMan((R)) reverse transcription polymerase chain reaction and immunofluorescent microscopy. 52 tumors (53%) contained iNKTs, and oligonucleotide microarray analysis of the iNKT(+) and iNKT(-) tumors revealed that the former expressed higher levels of CCL2/MCP-1, CXCL12/SDF-1, CCL5/RANTES, and CCL21/SLC. Eight tested neuroblastoma cell lines secreted a range of CCL2 (0-21.6 ng/ml), little CXCL12 (</=0.1 ng/ml), and no detectable CCL5 or CCL21. CCR2, the receptor for CCL2, was more frequently expressed by iNKT compared with natural killer and T cells from blood (P < 0.001). Supernatants of neuroblastoma cell lines that produced CCL2 induced in vitro migration of iNKTs from blood of patients and normal adults; this was abrogated by an anti-CCL2 monoclonal antibody. CCL2 expression by tumors was found to inversely correlate with MYCN proto-oncogene amplification and expression (r = 0.5, P < 0.001), and MYCN-high/CCL2-low expression accurately predicted the absence of iNKTs (P < 0.001). In summary, iNKTs migrate toward neuroblastoma cells in a CCL2-dependent manner, preferentially infiltrating MYCN nonamplified tumors that express CCL2.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

CD1d-restricted T-cell subsets and dendritic cell function in autoimmunity.

CD1-restricted T cells have been shown to play a critical role in host defence, tumour surveillance, and maintenance of tolerance. However, immunologic outcomes resulting from activation of CD1d-restricted T cells can be either beneficial or deleterious. A major mechanism by which CD1d-restricted T cells are thought to exert immunoregulatory control is via effects on dendritic cell (DC) differentiation and migration. Important functional subsets of CD1d-restricted T cells are also known to exist and the potential implications for preferential subset activations are discussed.

Animals↗
PubMed2003

Disseminated varicella infection due to the vaccine strain of varicella-zoster virus, in a patient with a novel deficiency in natural killer T cells.

An 11-year-old girl presented with a papulovesicular rash and severe respiratory distress 5 weeks after receiving varicella vaccine. Restriction fragment length-polymorphism analysis of virus isolated from an endotracheal-tube aspirate and from bronchoalveolar lavage revealed that this patient's illness was due to the Oka vaccine strain of varicella. An extensive immunologic analysis failed to identify a known diagnostic entity to explain her susceptibility to this attenuated vaccine strain. Analysis of her lymphocytes on separate occasions, months after recovery from her illness, revealed a profound deficiency of natural killer T (NKT) cells and of NKT-cell activity, suggesting that NKT cells contribute to host defense against varicella virus.

Antigens, Viral↗
PubMed2003

Phenotypic and functional characterization of long-term cultured rhesus macaque spleen-derived NKT cells.

Natural killer T cells are immunoregulatory cells, which have important roles in tolerance and autoimmunity, as demonstrated primarily in mice and humans. In this study, we define the phenotype and function of Valpha24(+) T cells derived from the spleens of rhesus macaques, a species increasingly used in models of immune tolerance. Valpha24(+) cells were isolated and expanded with monocyte-derived immature dendritic cells in the presence of alpha-galactosylceramide, IL-2, and IL-15. Rhesus NKT cells were stained with mAbs against both Valpha24 and the invariant complementarity-determining region 3 epitope of the human Valpha24/JalphaQ TCR. The cells were CD4, CD8 double negative and expressed CD56. Rhesus NKT cells also exhibited moderate to high expression of CD95, CD45RO, CD11a, and beta(7) integrin, but did not express CD45 RA, CD62L, CCR7, CD28, and other activation, costimulatory molecules (CD69 and CD40L). By intracellular staining, >90% of unstimulated rhesus NKT cells expressed IL-10, but not IFN-gamma. However, the latter was strongly expressed after stimulation. Rhesus NKT secreted large amounts of TGF-beta, IL-13, and IL-6, and modest levels of IFN-gamma, whereas IL-10 secretion was negligible and no detectable IL-4 was observed either intracellularly or in culture supernatants. Functionally, the NKT cells and their supernatants suppressed T cell proliferation in allogeneic MLR. We conclude that long-term cultured rhesus macaque spleen-derived Valpha24(+) T cells are semi-invariant double-negative cells with effector memory phenotype. These cells are semianergic, polarized to a uniquely Th3 > T regulatory-1 regulatory cell phenotype, and have regulatory/suppressive function in vitro.

Animals↗
PubMed2003

CD1d-restricted NKT cells express a chemokine receptor profile indicative of Th1-type inflammatory homing cells.

CD1d-restricted T cells (NKT cells) are innate memory cells activated by lipid Ags and play important roles in the initiation and regulation of the immune response. However, little is known about the trafficking patterns of these cells or the tissue compartment in which they exert their regulatory activity. In this study, we determined the chemokine receptor profile expressed by CD1d-restricted T cells found in the peripheral blood of healthy volunteers as well as CD1d-restricted T cell clones. CD1d-restricted T cells were identified by Abs recognizing the invariant Valpha24 TCR rearrangement or by binding to CD1d-Fc fusion tetramers loaded with alpha-GalCer. CD1d-restricted T cells in the peripheral blood and CD1d-restricted T cell clones expressed high levels of CXCR3, CCR5, and CCR6; intermediate levels of CXCR4 and CXCR6; and low levels of CXCR1, CCR1, CCR2, and CX(3)CR1, a receptor pattern often associated with tissue-infiltrating effector Th1 cells and CD8+ T cells. Very few of these cells expressed the lymphoid-homing receptors CCR7 or CXCR5. CCR4 was expressed predominantly on CD4+, but not on double-negative CD1d-restricted T cells, which may indicate differential trafficking patterns for these two functionally distinct subsets. CD1d-restricted T cell clones responded to chemokine ligands for CXCR1/2, CXCR3, CXCR4, CXCR6, CCR4, and CCR5 in calcium flux and/or chemotaxis assays. These data indicate that CD1d-restricted T cells express a chemokine receptor profile most similar to Th1 inflammatory homing cells and suggest that these cells perform their function in peripheral tissue sites rather than in secondary lymphoid organs.

Animals↗
PubMed2003

CD1d-restricted T cells regulate dendritic cell function and antitumor immunity in a granulocyte-macrophage colony-stimulating factor-dependent fashion.

CD1d-restricted T cells contribute to tumor protection, but their precise roles remain unclear. Here we show that tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor induce the expansion of CD1d-restricted T cells through a mechanism that involves CD1d and macrophage inflammatory protein 2 expression by CD8 alpha-, CD11c+ dendritic cells (DCs). The antitumor immunity stimulated by vaccination with irradiated, granulocyte-macrophage colony-stimulating factor-secreting tumor cells was abrogated in CD1d- and J alpha 281-deficient mice, revealing a critical role for CD1d-restricted T cells in this response. The loss of antitumor immunity was associated with impaired tumor-induced T helper 2 cytokine production, although IFN-gamma secretion and cytotoxicity were preserved. DCs from immunized CD1d-deficient mice showed compromised maturation and function. Together, these results delineate a role for CD1d-restricted T cell-DC cross talk in the shaping of antitumor immunity.

Animals↗
PubMed2003

Janus-like role of regulatory iNKT cells in autoimmune disease and tumour immunity.

Invariant CD1D-restricted natural killer T (iNKT) cells function during innate and adaptive immunity and regulate numerous immune responses, such as autoimmune disease, tumour surveillance, infectious disease and abortions. However, the molecular basis of their functions and the nature of disease-associated defects of iNKT cells are unclear and have been the subject of recent controversy. Here, we review recent findings that underscore the potential importance of interactions between iNKT cells and dendritic cells (DCs) that indicate that iNKT cells regulate DC activity to shape both pro-inflammatory and tolerogenic immune responses. The ability to modulate iNKT-cell activity in vivo using the ligand alpha-galactosylceramide and to treat patients with autoimmune disease or cancer is evaluated also.

Animals↗
PubMed2003

Interleukin-12 and interleukin-2-induced invariant natural killer T-cell cytokine secretion and perforin expression independent of T-cell receptor activation.

Human invariant natural killer (iNK) T cells expressing an invariant Valpha24-Jalpha15 T-cell receptor (TCR) are thought to be important regulators of autoimmunity and tumour surveillance. Two major subsets of iNK T cells, CD4+ or CD4- CD8- are known to exist, but the in vivo importance of CD4 expression is unclear. Since interleukin-12 (IL-12) is a key iNK T-cell-activating cytokine, the effect of IL-12 plus or minus the T-cell growth factor IL-2 on a large panel of CD4+ versus CD4- CD8- iNK T-cell clones was examined. Strikingly, IL-12 and IL-2 significantly activated iNK T cells to secrete IL-4, interferon-gamma and granulocyte-macrophage colony-stimulating factor, and up-regulated perforin expression in the absence of TCR stimulation. Furthermore, IL-2 and IL-12 treatment resulted in a preferential increase in apoptosis of CD4- CD8- clones. Thus, independent of TCR activation, IL-2 and IL-12 can directly activate iNK T cells and provide a selective advantage to the CD4+ iNK T-cell population.

Apoptosis↗
PubMed2002

TCR gamma delta+ and CD161+ thymocytes express HIV-1 in the SCID-hu mouse, potentially contributing to immune dysfunction in HIV infection.

The vast diversity of the T cell repertoire renders the adaptive immune response capable of recognizing a broad spectrum of potential antigenic peptides. However, certain T cell rearrangements are conserved for recognition of specific pathogens, as is the case for TCRgammadelta cells. In addition, an immunoregulatory class of T cells expressing the NK receptor protein 1A (CD161) responds to nonpeptide Ags presented on the MHC-like CD1d molecule. The effect of HIV-1 infection on these specialized T cells in the thymus was studied using the SCID-hu mouse model. We were able to identify CD161-expressing CD3(+) cells but not the CD1d-restricted invariant Valpha24/Vbeta11/CD161(+) NK T cells in the thymus. A subset of TCRgammadelta cells and CD161-expressing thymocytes express CD4, CXCR4, and CCR5 during development in the thymus and are susceptible to HIV-1 infection. TCRgammadelta thymocytes were productively infectable by both X4 and R5 virus, and thymic HIV-1 infection induced depletion of CD4(+) TCRgammadelta cells. Similarly, CD4(+)CD161(+) thymocytes were depleted by thymic HIV-1 infection, leading to enrichment of CD4(-)CD161(+) thymocytes. Furthermore, compared with the general CD4-negative thymocyte population, CD4(-)CD161(+) NK T thymocytes exhibited as much as a 27-fold lower frequency of virus-expressing cells. We conclude that HIV-1 infection and/or disruption of cells important in both innate and acquired immunity may contribute to the overall immune dysfunction seen in HIV-1 disease.

Animals↗
PubMed2002

CD1d and invariant NKT cells at the human maternal-fetal interface.

Invariant CD1d-restricted natural killer T (iNKT) cells comprise a small, but significant, immunoregulatory T cell subset. Here, the presence of these cells and their CD1d ligand at the human maternal-fetal interface was investigated. Immunohistochemical staining of human decidua revealed the expression of CD1d on both villous and extravillous trophoblasts, the fetal cells that invade the maternal decidua. Decidual iNKT cells comprised 0.48% of the decidual CD3+ T cell population, a frequency 10 times greater than that seen in peripheral blood. Interestingly, decidual CD4+ iNKT cells exhibited a striking Th1-like bias (IFN-gamma production), whereas peripheral blood CD4+ iNKT clones exhibited a Th2-like bias (IL-4 production). Moreover, compared to their peripheral blood counterparts, decidual iNKT clones were strongly polarized toward granulocyte/macrophage colony-stimulating factor production. The demonstration of CD1d expression on fetal trophoblasts together with the differential pattern of cytokine expression by decidual iNKT cells suggests that maternal iNKT cell interactions with CD1d expressed on invading fetal cells may play an immunoregulatory role at the maternal-fetal interface.

Antigens, CD1↗
PubMed2002

Control of myeloid dendritic cell differentiation and function by CD1d-restricted (NK) T cells.

While regulating a wide variety of immunologic responses, the precise immunologic functions of CD1d-restricted (NK) T cells are not well defined. Notably, In vitro activation of human NK T cell clones results in the secretion of multiple cytokines important for the recruitment and differentiation of myeloid dendritic cells (DC). Once differentiated, these DC strongly activate NK T cells. In humans, CD1d is expressed by myeloid DC and on tumor cells of this lineage. Another specialized myeloid antigen presenting cell, the epithelioid histiocyte seen in granulomatous inflammation, also expresses CD1d. Because myeloid DC are important regulators of Th1/Th2 T cell responses, cross talk between human NK T cells and myeloid DC would be expected to have significant impact on many immune responses. Consistent with this hypothesis, NK T cells are required for myeloid DC-controlled antitumor responses in mice, and regulate diabetes in nonobese diabetic (NOD) mouse by locally controlling the frequency and function of DC subsets. Thus, regulation of myeloid DC by NK T cells controls both the transition from innate to adaptive immunity and the Th-phenotype of subsequent T cell responses.

Animals↗
PubMedDate not supplied

Regulation of dendritic cell subsets by NKT cells.

NKT cells expressing both invariant TCRs and NK cell receptors are an important regulatory cell subset active during initiation of innate immune responses. They are involved in a wide variety of immune responses, but the molecular details of their regulatory action are unknown. Transcriptional profiling has been used for analysis of NKT cell activation profiles, revealing that NKT cells differ from conventional T cells and would be expected to regulate immune responses by controlling dendritic cell activation.

Dendritic Cells↗