Retrovirally induced CTL degranulation mediated by IL-15 expression and infection of mononuclear phagocytes in patients with HTLV-I–associated neurologic disease

Enose-Akahata, Yoshimi; Oh, Unsong; Grant, Christian; Jacobson, Steven

doi:10.1182/blood-2008-02-138529

Cited by 34 publications

(66 citation statements)

References 76 publications

(77 reference statements)

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“…This suggested that MHC class II was probably a participant in the interaction between leukemic cells and monocytes. CD14 ϩ monocytes can be infected by HTLV-I virus 34 ; moreover, in HAM/TSP, CD14 ϩ monocytes provided a signal for virus-specific CD8 cell expansion and cytotoxic T-lymphocyte degranulation in a MHC class I-restricted manner in the ex vivo cultures. 34 Although the virus-specific CD4 T-cell response in HAM/TSP has not been analyzed, it would be interesting to investigate virus-specific CD4 cell expansion in patients with ATL.…”

Section: Discussionmentioning

confidence: 99%

Autocrine/paracrine cytokine stimulation of leukemic cell proliferation in smoldering and chronic adult T-cell leukemia

Chen

Petrus

Bryant

et al. 2010

Blood

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Interestingly, the addition of an anti-IL-2R-␣ monoclonal antibody profoundly inhibited IL-9 expression, suggesting optimal expression of IL-9 was dependent on IL-2 signaling in these patients. To determine whether there would be autonomous proliferation of ATL leukemic cells, we purified leukemic cells from patients with smoldering/chronic ATL. Purified leukemic cells cultured alone produced IL-2/ IL-9, and the downstream Janus kinase/ signal transducer and activator of transcription pathway was activated. However, the leukemic cells did not proliferate independently, but required coculture with autologous monocytes to induce proliferation. Moreover, interaction between leukemic cells and monocytes was contact dependent, and major histocompatibility complex class II expression may have contributed to this interaction. In conclusion, our data provide evidence that there is autocrine/paracrine cytokine stimulation of leukemic cell proliferation in patients with smoldering/chronic ATL that could be targeted for treatment. IntroductionAdult T-cell leukemia (ATL) that is caused by human T-cell lymphotropic virus I (HTLV-1) is an aggressive malignancy of CD4-and CD25-expressing leukemia, and lymphoma cells. ATL is a heterogeneous disease that can be divided broadly into 4 stages: smoldering, chronic, lymphoma, and acute-type ATL. The common clinical manifestations of ATL are skin lesions, hypercalcemia, immunologic anergy to antigen stimulation, and cells with "flowerlike" nuclei in the circulation. Smoldering/chronic ATL patients have normal or mildly increased white blood cell counts with a variable number of leukemic cells in the circulation and are generally associated with a better prognosis. Patients with acutetype ATL have organ dysfunction associated with circulating leukemic cells and are generally associated with a poor prognosis. The mechanisms underlying the progression from smoldering/chronic stage to the acute stage are unknown; however, the accumulation of molecular mutations is thought to play a role in this progression.Although the pathogenesis of ATL is unknown, the virally encoded regulatory protein, HTLV-1 Tax, seems to play a central role in the initial leukemogenesis of ATL. Hasegawa et al demonstrated that overexpression of Tax in immature thymocytes induced leukemia/lymphoma in mice with clinical, pathologic, and immunologic features characteristic of ATL after a long latency. 1 Subsequently, Ohsugi et al 2 showed that Tax is able to promote oncogenesis not only with immature T cells, but also with mature T cells. Both experiments highlighted the importance of Tax in the initial development of ATL.Beyond the in vivo mouse models, numerous in vitro studies have demonstrated the essential role of Tax in ATL initiation and shed light on the mechanism of Tax-mediated cellular transformation. 3 Tax deregulates the expression of genes involved in cellular proliferation, cell-cycle control, and apoptosis through physical interaction with cellular elements, including transcription factors such as nuc...

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Section: Discussionmentioning

confidence: 99%

Autocrine/paracrine cytokine stimulation of leukemic cell proliferation in smoldering and chronic adult T-cell leukemia

Chen

Petrus

Bryant

et al. 2010

Blood

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“…HAM/TSP PBMCs were stained with A B For spontaneous CTL degranulation, HAM/TSP PBMCs were cultured in a 96-well U-bottom plate at 2 × 10 5 cells per well, with or without BNZ132-1-40 10 μM, and analysis was performed as previously described (19).…”

Section: Methodsmentioning

confidence: 99%

“…+ CTLs in unstimulated ex vivo culture compared with asymptomatic carriers and healthy donors (19 (19). Therefore, it was of interest to examine the effects of BNZ132-1-40 on the frequency of CD107a (a marker of the mobilization of cytolytic granules to the cell surface) and the production of IFN-γ by CD8…”

Section: Bnz132-1-40 Reduces Htlv-1-induced Cytolytic T-cell Degranulmentioning

confidence: 99%

Common γ-chain blocking peptide reduces in vitro immune activation markers in HTLV-1-associated myelopathy/tropical spastic paraparesis

Massoud

Enose-Akahata

Tagaya

et al. 2015

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

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Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive inflammatory myelopathy occurring in a subset of HTLV-1-infected individuals. Despite advances in understanding its immunopathogenesis, an effective treatment remains to be found. IL-2 and IL-15, members of the gamma chain (γc) family of cytokines, are prominently deregulated in HAM/TSP and underlie many of the characteristic immune abnormalities, such as spontaneous lymphocyte proliferation (SP), increased STAT5 phosphorylation in the lymphocytes, and increased frequency and cytotoxicity of virus-specific cytotoxic CD8+ T lymphocytes (CTLs). In this study, we describe a novel immunomodulatory strategy consisting of selective blockade of certain γc family cytokines, including IL-2 and IL-15, with a γc antagonistic peptide. In vitro, a PEGylated form of the peptide, named BNZ132-1-40, reduced multiple immune activation markers such as SP, STAT5 phosphorylation, spontaneous degranulation of CD8 + T cells, and the frequency of transactivator protein (Tax)-specific CD8 + CTLs, thought to be major players in the immunopathogenesis of the disease. This strategy is thus a promising therapeutic approach to HAM/TSP with the potential of being more effective than single monoclonal antibodies targeting either IL-2 or IL-15 receptors and safer than inhibitors of downstream signaling molecules such as JAK1 inhibitors. Finally, selective cytokine blockade with antagonistic peptides might be applicable to multiple other conditions in which cytokines are pathogenic.human T-cell lymphotropic virus type 1 | HAM/TSP | gamma chain | IL-15

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“…Infected DCs have been shown to effectively transmit viruses to CD4 ϩ T cells (26,27). Moreover, HTLV-1-infected DCs can stimulate CD4 ϩ and CD8 ϩ T cells (29), and infection of CD14 ϩ cells with the concomitant expression of interleukin-15 (IL-15) mediates spontaneous degranulation and gamma interferon (IFN-␥) production in CD8 ϩ T cells (30). Furthermore, the maturation of DCs seems to be inhibited in HTLV-1-infected patients, which could contribute to the complex immune dysregulation that underlies HTLV-1 pathogenesis (31,32).…”

mentioning

confidence: 99%

“…Monocytes are precursors of tissue macrophages and dendritic cells and play a central role in the immune response to pathogens. Monocytes can be infected in vitro and in vivo by HTLV-1 (26,29,30,(33)(34)(35)(36)(37)(38)(39)(40). Furthermore, studies with nonhuman primates indicate that monocyte infection, which depends on the expression of the viral orf-I-encoded p8 and p12 proteins and the viral p30 protein, is pivotal for viral infectivity and persistence in vivo (38,40,41).…”

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confidence: 99%

Human T Cell Leukemia Virus Type 1 Infection of the Three Monocyte Subsets Contributes to Viral Burden in Humans

Castro-Amarante

Pise-Masison

McKinnon

et al. 2016

J Virol

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A pproximately 2 to 3% of human T cell leukemia virus type 1 (HTLV-1)-infected individuals develop adult T-cell leukemia/lymphoma (ATL) and another 2 to 3% develop HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) in their lifetimes (1-4). In addition to HAM/TSP (5, 6), HTLV-1 is also associated with other inflammatory conditions, such as uveitis (6) Sjögren's syndrome (7), bronchoalveolitis and arthritis (8), and polymyositis (9). It is noteworthy that some patients present with more than one of these inflammatory conditions (10). HTLV-1 primarily infects CD4 ϩ and CD8 ϩ effector and memory T cells and regulatory CD4 ϩ CD25 ϩ T cells (11,12). A high viral DNA burden in peripheral blood mononuclear cells (PBMCs) is a risk factor for HAM/TSP (13) and ATL development (14-16), and patients with HAM/TSP have a higher virus level in the cerebrospinal fluid (CSF) than in the peripheral blood (12). The virus level alone is not sufficient to differentiate symptomatic patients from healthy carriers, suggesting the importance of other factors, including the host immune response (16)(17)(18)(19)(20). HAM/TSP patients present diverse immunological alterations, such as increased levels of spontaneous lymphocyte proliferation (21, 22), tax-specific cytotoxic CD8 ϩ T cell expansion, and the production of high levels of inflammatory cytokines (23)(24)(25). Several studies have also suggested that monocytes are involved in immune reg-

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Retrovirally induced CTL degranulation mediated by IL-15 expression and infection of mononuclear phagocytes in patients with HTLV-I–associated neurologic disease

Cited by 34 publications

References 76 publications

Autocrine/paracrine cytokine stimulation of leukemic cell proliferation in smoldering and chronic adult T-cell leukemia

Autocrine/paracrine cytokine stimulation of leukemic cell proliferation in smoldering and chronic adult T-cell leukemia

Common γ-chain blocking peptide reduces in vitro immune activation markers in HTLV-1-associated myelopathy/tropical spastic paraparesis

Human T Cell Leukemia Virus Type 1 Infection of the Three Monocyte Subsets Contributes to Viral Burden in Humans

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