iNKT Cells Suppress the CD8+ T Cell Response to a Murine Burkitt’s-Like B Cell Lymphoma

Mayo Clinic, United States of America
PLoS ONE (Impact Factor: 3.23). 08/2012; 7(8):e42635. DOI: 10.1371/journal.pone.0042635
Source: PubMed


The T cell response to B cell lymphomas differs from the majority of solid tumors in that the malignant cells themselves are derived from B lymphocytes, key players in immune response. B cell lymphomas are therefore well situated to manipulate their surrounding microenvironment to enhance tumor growth and minimize anti-tumor T cell responses. We analyzed the effect of T cells on the growth of a transplantable B cell lymphoma and found that iNKT cells suppressed the anti-tumor CD8(+) T cell response. Lymphoma cells transplanted into syngeneic wild type (WT) mice or Jalpha18(-/-) mice that specifically lack iNKT cells grew initially at the same rate, but only the mice lacking iNKT cells were able to reject the lymphoma. This effect was due to the enhanced activity of tumor-specific CD8(+) T cells in the absence of iNKT cells, and could be partially reversed by reconstitution of iNKT cells in Jalpha 18(-/-) mice. Treatment of tumor-bearing WT mice with alpha -galactosyl ceramide, an activating ligand for iNKT cells, reduced the number of tumor-specific CD8(+) T cells. In contrast, lymphoma growth in CD1d1(-/-) mice that lack both iNKT and type II NKT cells was similar to that in WT mice, suggesting that type II NKT cells are required for full activation of the anti-tumor immune response. This study reveals a tumor-promoting role for iNKT cells and suggests their capacity to inhibit the CD8(+) T cell response to B cell lymphoma by opposing the effects of type II NKT cells.

Download full-text


Available from: Yosef Refaeli, May 22, 2015
  • Source
    • "Bjordahl et al. found that mice lacking iNKT cells were able to reject lymphoma [32], and proposed that this effect was due to tumor-specific CD8+ T cells being suppressed by iNKT cells. We believe that the role of iNKT cells is more nuanced. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Natural killer T (NKT) cells are a unique subset of CD1d-restricted T lymphocytes that express characteristics of both T cells and natural killer cells. NKT cells mediate tumor immune-surveillance; however, NKT cells are numerically reduced and functionally impaired in lymphoma patients. Many hematologic malignancies express CD1d molecules and co-stimulatory proteins needed to induce anti-tumor immunity by NKT cells, yet most tumors are poorly immunogenic. In this study, we sought to investigate NKT cell responses to B cell lymphoma. In the presence of exogenous antigen, both mouse and human NKT cell lines produce cytokines following stimulation by B cell lymphoma lines. NKT cell populations were examined ex vivo in mouse models of spontaneous B cell lymphoma, and it was found that during early stages, NKT cell responses were enhanced in lymphoma-bearing animals compared to disease-free animals. In contrast, in lymphoma-bearing animals with splenomegaly and lymphadenopathy, NKT cells were functionally impaired. In a mouse model of blastoid variant mantle cell lymphoma, treatment of tumor-bearing mice with a potent NKT cell agonist, α-galactosylceramide (α-GalCer), resulted in a significant decrease in disease pathology. Ex vivo studies demonstrated that NKT cells from α-GalCer treated mice produced IFN-γ following α-GalCer restimulation, unlike NKT cells from vehicle-control treated mice. These data demonstrate an important role for NKT cells in the immune response to an aggressive hematologic malignancy like mantle cell lymphoma.
    06/2014; 2(2):82-97. DOI:10.3390/medsci2020082
  • Source
    • "However, in L. monocytogenes infection the role of NKT cells is unclear with studies showing better as well as diminished control of listeria in the absence of NKT cells [28]–[30]. In addition, there is also evidence for a suppressive role of NKT cells [31]–[33] and the CXCL16/CXCR6 axis might be a central regulatory element of this function. We could recently demonstrate that absence of CXCR6 causes aggravation of autoimmune kidney inflammation which was mainly due to diminished recruitment of regulatory NKT cells to the kidney [34]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The chemokine receptor CXCR6 is expressed on different T cell subsets and up-regulated following T cell activation. CXCR6 has been implicated in the localization of cells to the liver due to the constitutive expression of its ligand CXCL16 on liver sinusoidal endothelial cells. Here, we analyzed the role of CXCR6 in CD8+ T cell responses to infection of mice with Listeria monocytogenes. CD8+ T cells responding to listerial antigens acquired high expression levels of CXCR6. However, deficiency of mice in CXCR6 did not impair control of the L. monocytogenes infection. CXCR6-deficient mice were able to generate listeria-specific CD4+ and CD8+ T cell responses and showed accumulation of T cells in the infected liver. In transfer assays, we detected reduced accumulation of listeria-specific CXCR6-deficient CD8+ T cells in the liver at early time points post infection. Though, CXCR6 was dispensable at later time points of the CD8+ T cell response. When transferred CD8+ T cells were followed for extended time periods, we observed a decline in CXCR6-deficient CD8+ T cells. The manifestation of this cell loss depended on the tissue analyzed. In conclusion, our results demonstrate that CXCR6 is not required for the formation of a T cell response to L. monocytogenes and for the accumulation of T cells in the infected liver but CXCR6 appears to influence long-term survival and tissue distribution of activated cells.
    PLoS ONE 05/2014; 9(5):e97701. DOI:10.1371/journal.pone.0097701 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Accumulating evidence indicates that Lymphotoxin (LT)-β related cytokines directly contribute to the phenotype of cancer cells and alter the tumor microenvironment. Lymphotoxins are part of a cytokine network well known in controlling the development and homeostasis of secondary lymphoid organs. In the adult, the LT network takes on the responsibility of generating inflammatory microenvironments that control innate and adaptive immune responses involved in host defense. This review provides a perspective of the emerging evidence implicating the LT Network in the development and progression of various cancers including lymphoma. Redirecting the LT Network to alter tumor microenvironments may provide a specific approach to therapeutically target tumor-permissive microenvironments and cancer progression.
    Current opinion in immunology 01/2013; 25(2). DOI:10.1016/j.coi.2013.01.001 · 7.48 Impact Factor
Show more