Transforming Growth Factor-β Production and Myeloid Cells Are an Effector Mechanism through Which CD1d-restricted T Cells Block Cytotoxic T Lymphocyte–mediated Tumor Immunosurveillance

Terabe, Masaki; Matsui, Shusuke; Park, Jong-Myun; Mamura, Mizuko; Noben-Trauth, Nancy; Donaldson, Debra D.; Chen, Wanjun; Wahl, Sharon M.; Ledbetter, Steven; Pratt, Bruce M.; Letterio, John J.; Paul, William E.; Berzofsky, Jay A.

doi:10.1084/jem.20022227

Cited by 506 publications

(447 citation statements)

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“…Similar cell lineages have been identified in various models: recombinant virusimmunized mice, and tumor bearing mice. 31,32 However, the mechanisms by which these immunosupressive factors are induced remain unclear. TGF-b entertains a complicated relationship with T-cell activation and death.…”

Section: Discussionmentioning

confidence: 99%

TGF-β in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus

et al. 2007

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SIV-infected macaques exhibit distinct rates of progression to AIDS and despite significant increases in CD8 þ T cells, immune cells fail to control and eradicate SIV in vivo. Here, we investigated the interplay between viral reservoir sites, CD8 þ T-cell activation/death and outcome. Our data provide strong evidence that mesenteric (Mes) lymph nodes represent major reservoirs not only for SIV-infected macaques progressing more rapidly toward AIDS but also in controllers. We demonstrate that macaques progressing faster display greater expression of TGF-b and Indoleamine 2,3 dioxygenase in particular in intestinal tissues associated with a phosphorylation of the p53 protein on serine 15 in CD8 þ T cells from Mes lymph nodes. These factors may act as a negative regulator of CD8 þ T-cell function by inducing a Bax/Bak/Puma-dependent death pathway of effector/ memory CD8 þ T cells. Greater T-cell death and viral dissemination was associated with a low level of TIA-1 þ expressing cells. Finally, we provide evidence that abrogation of TGF-b in vitro enhances T-cell proliferation and reduces CD8 þ T-cell death. Our data identify a mechanism of T-cell exhaustion in intestinal lymphoid organs and define a potentially effective immunological strategy for the modulation of progression to AIDS. Cell Death and Differentiation (2007) 14, 1747-1758; doi:10.1038/sj.cdd.4402192; published online 6 July 2007Virus production in Human Immunodeficiency Virus 1 (HIV-1)-infected individuals is largely the result of a dynamic process involving continuous rounds of de novo infection and replication in CD4 þ cells with rapid turnover of both free virus and virus producing cells. Moreover, an increasing body of evidence suggests that reservoirs, cell types or anatomical sites ('sanctuaries'), represent a major barrier to virus eradication. 1 HIV-specific CD8 þ T lymphocytes (CTL) are considered crucial in the control of viral replication. 2 Excessive induction of apoptosis has been proposed as one major mechanism of abnormal T-cell response during HIV and Simian Immunodeficiency Virus (SIV) infections. 3 However, most studies, which investigated the potential relationship between HIV and SIV infections and apoptosis have focused on cells from peripheral blood, rather than on cells from lymphoid organs.Peripheral lymphoid tissues such as the axillary and inguinal (Ing) lymph nodes (LNs), which drain the arms and legs, respectively, and the spleen, are considered major sites of HIV/SIV replication. 4 Accumulating data also indicate that gut-associated lymphoid tissue (GALT), which contains inductive sites, Peyer's patches and mesenteric (Mes) LNs, and effectors sites located within lamina propria and epithelium of the intestinal wall, is also an early and predominant tissue site of viral replication and may be a reservoir for HIV/SIV. 5,6 Because T cells from the GALT are required to maintain a state of immunological tolerance toward a myriad of dietary and resident bacterial antigens, the chronic exposure of HIV/ SIV-specific antigens coul...

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Section: Discussionmentioning

confidence: 99%

TGF-β in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus

et al. 2007

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“…IMC are present in bone marrow and spleens of healthy mice, and under normal conditions differentiate into mature myeloid cells (12). However, they accumulate in large numbers in tumor-bearing mice probably due to the effect of various tumor-derived factors (13)(14)(15)(16)(17)(18). Gr-1 ϩ IMC freshly isolated from spleen of tumor-bearing mice could not inhibit CD4-mediated T cell response, but were able to suppress CD8 ϩ T cells in Ag-dependent manner (16).…”

Section: Stat1 Signaling Regulates Tumor-associated Macrophage-mediatmentioning

confidence: 99%

STAT1 Signaling Regulates Tumor-Associated Macrophage-Mediated T Cell Deletion

Kusmartsev

Gabrilovich

2005

The Journal of Immunology

389

325

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It is well established that tumor progression is associated with the accumulation of myeloid suppressive cells, which in mice include Gr-1+ immature myeloid cells and F4/80+ macrophages. The paradox is that with the exception of terminal stages of the disease or chemotherapy treatment, tumor-bearing mice or cancer patients do not display a profound systemic immune suppression. We therefore raised the question as to whether myeloid cell-mediated T cell suppression is controlled at a local level at the site of the tumor. We have demonstrated that after adoptive transfer to tumor-bearing recipients, Gr-1+ (immature myeloid cells) freshly isolated from spleens of tumor-bearing mice become F4/80+ tumor-associated macrophages (TAM). These TAM, but not F4/80+ macrophages or Gr-1+ cells freshly isolated from spleens of tumor-bearing or naive mice were able to inhibit T cell-mediated immune response in vitro via induction of T cell apoptosis. Arginase and NO were both responsible for the apoptotic mechanism, and were seen only in TAM, but not in freshly isolated Gr1+ cells. Using the analysis of STAT activity in combination with STAT knockout mice, we have determined that STAT1, but not STAT3 or STAT6, was responsible for TAM-suppressive activity.

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“…In TGFβRII transgenic mice, loss of TGF-β signaling in T cells resulted in the generation of tumor-specific CTL responses which otherwise would be repressed [31]. TGF-β can repress CTL through blunting expression of cytolytic gene products [32], through a mechanism involving CD1d-resticted natural killer T cells(NKT) in concert with IL-13 [33], and also through induction of Treg.…”

Section: Tgf-β Suppression Of Tumor Immunitymentioning

confidence: 99%