Background Human T-lymphotropic virus type 1 (HTLV-1) is a human retrovirus associated with both HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), which is a chronic neuroinflammatory disease, and adult T-cell leukemia (ATL). The pathogenesis of HAM/TSP is known to be as follows: HTLV-1-infected T cells trigger a hyperimmune response leading to neuroinflammation. However, the HTLV-1-infected T cell subset that plays a major role in the accelerated immune response has not yet been identified. Principal Findings Here, we demonstrate that CD4+CD25+CCR4+ T cells are the predominant viral reservoir, and their levels are increased in HAM/TSP patients. While CCR4 is known to be selectively expressed on T helper type 2 (Th2), Th17, and regulatory T (Treg) cells in healthy individuals, we demonstrate that IFN-γ production is extraordinarily increased and IL-4, IL-10, IL-17, and Foxp3 expression is decreased in the CD4+CD25+CCR4+ T cells of HAM/TSP patients as compared to those in healthy individuals, and the alteration in function is specific to this cell subtype. Notably, the frequency of IFN-γ-producing CD4+CD25+CCR4+Foxp3？ T cells is dramatically increased in HAM/TSP patients, and this was found to be correlated with disease activity and severity. Conclusions We have defined a unique T cell subset—IFN-γ+CCR4+CD4+CD25+ T cells—that is abnormally increased and functionally altered in this retrovirus-associated inflammatory disorder of the central nervous system.
References
[1]
Uchiyama T, Yodoi J, Sagawa K, Takatsuki K, Uchino H (1977) Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood 50: 481–492.
[2]
Kaplan JE, Osame M, Kubota H, Igata A, Nishitani H, et al. (1990) The risk of development of HTLV-1-associated myelopathy/tropical spastic paraparesis among persons infected with HTLV-1. J Acquir Immune Defic Syndr 3: 1096–1101.
[3]
Gessain A, Barin F, Vernant JC, Gout O, Maurs L, et al. (1985) Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet 2: 407–410.
[4]
Osame M, Usuku K, Izumo S, Ijichi N, Amitani H, et al. (1986) HTLV-I associated myelopathy, a new clinical entity. Lancet 1: 1031–1032.
[5]
Nishioka K, Maruyama I, Sato K, Kitajima I, Nakajima Y, et al. (1989) Chronic inflammatory arthropathy associated with HTLV-I. Lancet 1: 441.
[6]
Nakagawa M, Izumo S, Ijichi S, Kubota H, Arimura K, et al. (1995) HTLV-I-associated myelopathy: analysis of 213 patients based on clinical features and laboratory findings. J Neurovirol 1: 50–61.
[7]
Jacobson S, Shida H, McFarlin DE, Fauci AS, Koenig S (1990) Circulating CD8+ cytotoxic T lymphocytes specific for HTLV-I pX in patients with HTLV-I associated neurological disease. Nature 348: 245–248.
[8]
Yamano Y, Nagai M, Brennan M, Mora CA, Soldan SS, et al. (2002) Correlation of human T-cell lymphotropic virus type 1 (HTLV-1) mRNA with proviral DNA load, virus-specific CD8(+) T cells, and disease severity in HTLV-1-associated myelopathy (HAM/TSP). Blood 99: 88–94.
[9]
Furuya T, Nakamura T, Fujimoto T, Nakane S, Kambara C, et al. (1999) Elevated levels of interleukin-12 and interferon-gamma in patients with human T lymphotropic virus type I-associated myelopathy. J Neuroimmunol 95: 185–189.
[10]
Izumo S, Umehara F, Kashio N, Kubota R, Sato E, et al. (1997) Neuropathology of HTLV-1-associated myelopathy (HAM/TSP). Leukemia 11: Suppl 382–84.
[11]
Jacobson S (2002) Immunopathogenesis of human T cell lymphotropic virus type I-associated neurologic disease. J Infect Dis 186: Suppl 2S187–192.
[12]
Yamano Y, Cohen CJ, Takenouchi N, Yao K, Tomaru U, et al. (2004) Increased expression of human T lymphocyte virus type I (HTLV-I) Tax11-19 peptide-human histocompatibility leukocyte antigen A*201 complexes on CD4+CD25+T cells detected by peptide-specific, major histocompatibility complex-restricted antibodies in patients with HTLV-I-associated neurologic disease. J Exp Med 199: 1367–1377.
[13]
Koyanagi Y, Itoyama Y, Nakamura N, Takamatsu K, Kira J, et al. (1993) In vivo infection of human T-cell leukemia virus type I in non-T cells. Virology 196: 25–33.
[14]
Nagai M, Brennan MB, Sakai JA, Mora CA, Jacobson S (2001) CD8(+) T cells are an in vivo reservoir for human T-cell lymphotropic virus type I. Blood 98: 1858–1861.
[15]
Jones KS, Petrow-Sadowski C, Huang YK, Bertolette DC, Ruscetti FW (2008) Cell-free HTLV-1 infects dendritic cells leading to transmission and transformation of CD4(+) T cells. Nat Med 14: 429–436.
[16]
Enose-Akahata Y, Oh U, Grant C, Jacobson S (2008) Retrovirally induced CTL degranulation mediated by IL-15 expression and infection of mononuclear phagocytes in patients with HTLV-I-associated neurologic disease. Blood 112: 2400–2410.
[17]
Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, et al. (2006) Foxp3+CD25+CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev 212: 8–27.
[18]
Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299: 1057–1061.
[19]
Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA (2004) Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 199: 971–979.
[20]
Yamano Y, Takenouchi N, Li HC, Tomaru U, Yao K, et al. (2005) Virus-induced dysfunction of CD4+CD25+ T cells in patients with HTLV-I-associated neuroimmunological disease. J Clin Invest 115: 1361–1368.
[21]
Matsuoka M (2005) Human T-cell leukemia virus type I (HTLV-I) infection and the onset of adult T-cell leukemia (ATL). Retrovirology 2: 27.
[22]
Yoshie O, Fujisawa R, Nakayama T, Harasawa H, Tago H, et al. (2002) Frequent expression of CCR4 in adult T-cell leukemia and human T-cell leukemia virus type 1-transformed T cells. Blood 99: 1505–1511.
[23]
Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, et al. (2007) Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol 8: 639–646.
[24]
Hieshima K, Nagakubo D, Nakayama T, Shirakawa AK, Jin Z, et al. (2008) Tax-inducible production of CC chemokine ligand 22 by human T cell leukemia virus type 1 (HTLV-1)-infected T cells promotes preferential transmission of HTLV-1 to CCR4-expressing CD4+T cells. J Immunol 180: 931–939.
[25]
Okayama A, Stuver S, Matsuoka M, Ishizaki J, Tanaka G, et al. (2004) Role of HTLV-1 proviral DNA load and clonality in the development of adult T-cell leukemia/lymphoma in asymptomatic carriers. Int J Cancer 110: 621–625.
[26]
Yoshie O, Imai T, Nomiyama H (2001) Chemokines in immunity. Adv Immunol 78: 57–110.
[27]
Oh U, Grant C, Griffith C, Fugo K, Takenouchi N, et al. (2006) Reduced Foxp3 protein expression is associated with inflammatory disease during human t lymphotropic virus type 1 Infection. J Infect Dis 193: 1557–1566.
[28]
Hayashi D, Kubota R, Takenouchi N, Tanaka Y, Hirano R, et al. (2008) Reduced Foxp3 expression with increased cytomegalovirus-specific CTL in HTLV-I-associated myelopathy. J Neuroimmunol 200: 115–124.
[29]
Micha？lsson J, Barbosa HM, Jordan KA, Chapman JM, Brunialti MK, et al. (2008) The frequency of CD127low expressing CD4+CD25high T regulatory cells is inversely correlated with human T lymphotrophic virus type-1 (HTLV-1) proviral load in HTLV-1-infection and HTLV-1-associated myelopathy/tropical spastic paraparesis. BMC Immunol 9: 41.
[30]
Lee I, Wang L, Wells AD, Dorf ME, Ozkaynak E, et al. (2005) Recruitment of Foxp3+T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor. J Exp Med 201: 1037–1044.
[31]
Karube K, Ohshima K, Tsuchiya T, Yamaguchi T, Kawano R, et al. (2004) Expression of FoxP3, a key molecule in CD4CD25 regulatory T cells, in adult T-cell leukaemia/lymphoma cells. Br J Haematol 126: 81–84.
[32]
Hanon E, Goon P, Taylor GP, Hasegawa H, Tanaka Y, et al. (2001) High production of interferon gamma but not interleukin-2 by human T-lymphotropic virus type I-infected peripheral blood mononuclear cells. Blood 98: 721–726.
[33]
Nomoto M, Utatsu Y, Soejima Y, Osame M (1991) Neopterin in cerebrospinal fluid: a useful marker for diagnosis of HTLV-I-associated myelopathy/tropical spastic paraparesis. Neurology 41: 457.
[34]
Yoshida Y, Une F, Utatsu Y, Nomoto M, Furukawa Y, et al. (1999) Adenosine and neopterin levels in cerebrospinal fluid of patients with neurological disorders. Intern Med 38: 133–139.
[35]
Itoyama Y, Minato S, Kira J, Goto I, Sato H, et al. (1988) Spontaneous proliferation of peripheral blood lymphocytes increased in patients with HTLV-I-associated myelopathy. Neurology 38: 1302–1307.
[36]
Vine AM, Witkover AD, Lloyd AL, Jeffery KJ, Siddiqui A, et al. (2002) Polygenic control of human T lymphotropic virus type I (HTLV-I) provirus load and the risk of HTLV-I-associated myelopathy/tropical spastic paraparesis. J Infect Dis 186: 932–939.
[37]
Kohno T, Yamada Y, Akamatsu N, Kamihira S, Imaizumi Y, et al. (2005) Possible origin of adult T-cell leukemia/lymphoma cells from human T lymphotropic virus type-1-infected regulatory T cells. Cancer Sci 96: 527–533.
[38]
Nagai M, Kubota R, Greten TF, Schneck JP, Leist TP, et al. (2001) Increased activated human T cell lymphotropic virus type I (HTLV-I) Tax11-19-specific memory and effector CD8+ cells in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis: correlation with HTLV-I provirus load. J Infect Dis 183: 197–205.
[39]
Kannagi M (2007) Immunologic control of human T-cell leukemia virus type I and adult T-cell leukemia. Int J Hematol 86: 113–117.
[40]
Kubota R, Nagai M, Kawanishi T, Osame M, Jacobson S (2000) Increased HTLV type 1 tax specific CD8+ cells in HTLV type 1-asociated myelopathy/tropical spastic paraparesis: correlation with HTLV type 1 proviral load. AIDS Res Hum Retroviruses 16: 1705–1709.
[41]
Nagai M, Yamano Y, Brennan MB, Mora CA, Jacobson S (2001) Increased HTLV-I proviral load and preferential expansion of HTLV-I Tax-specific CD8+T cells in cerebrospinal fluid from patients with HAM/TSP. Ann Neurol 50: 807–812.
[42]
Chen S, Ishii N, Ine S, Ikeda S, Fujimura T, et al. (2006) Regulatory T cell-like activity of Foxp3+ adult T cell leukemia cells. Int Immunol 18: 269–277.
[43]
Wu Y, Borde M, Heissmeyer V, Feuerer M, Lapan AD, et al. (2006) FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126: 375–387.
[44]
Shimizu Y, Takamori A, Utsunomiya A, Kurimura M, Yamano Y, et al. (2009) Impaired Tax-specific T-cell responses with insufficient control of HTLV-1 in a subgroup of individuals at asymptomatic and smoldering stages. Cancer Sci 100(3): 481–489.
[45]
Toulza F, Heaps A, Tanaka Y, Taylor GP, Bangham CR (2008) High frequency of CD4+Foxp3+ cells in HTLV-1 infection: inverse correlation with HTLV-1 specific CTL response. Blood 111(10): 5047–5053.
[46]
Shimoyama M (1991) Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87). Br J Haematol 79: 428–437.
