The Impact of Immune Response on HTLV-I in HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP)

Document Type : Review Article

Authors

1 Inflammation and Inflammatory Diseases Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran

2 Allergy Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

 
 
Human T lymphotropic virus type I (HTLV-I) is a retrovirus which is associated with adult T cells leukaemia (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a minority of HTLV-I-infected individuals. It is not clear why a minority of HTLV-I-infected individuals develop HAM/TSP and majority remains lifelong carriers. It seems that the interaction between the virus and the immune response plays an important role in HTLV-I-associated diseases. Although the role of the immune response in HTLV-I pathogenesis is not fully understood, however it seems that the efficacy of the immune response which is involved in controlling or limiting of viral persistence determines the outcome of HTLV-I-associated diseases. Here we discuss the role of innate and adaptive immune response and also the risk factors contribute to the observed differences between HAM/TSP patients and asymptomatic HTLV-I carriers.
 

Keywords


Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD,Gallo RC.
Detection and isolation of type C retrovirus particles from fresh
and cultured lymphocytes of a patient with cutaneous T-cell
lymphoma. Proc Natl Acad Sci U S A 1980; 77:7415-7419.
2. Gessain A, Barin F, Vernant JC, Gout O, Maurs L, Calender A
 
, et al.
 
Antibodies to human T-lymphotropic virus type-I in patients
with tropical spastic paraparesis. Lancet 1985; 2:407-410.
3. Hinuma Y, Nagata K, Hanaoka M, Nakai M, Matsumoto T, Kinoshita
KI
, et al.
Adult T-cell leukemia: antigen in an ATL cell line and
detection of antibodies to the antigen in human sera. Proc Natl
 
Acad Sci U S A 1981; 78:6476-6480.
 
4. Proietti FA, Carneiro-Proietti AB, Catalan-Soares BC,Murphy EL.
 
Global epidemiology of HTLV-I infection and associated diseases.
 
Oncogene 2005; 24:6058-6068.
 
5. de The G,Bomford R. An HTLV-I vaccine: why, how, for whom?
 
AIDS Res Hum Retroviruses 1993; 9:381-386.
 
6. Hlela C, Shepperd S, Khumalo NP,Taylor GP. The prevalence of human
 
T-cell lymphotropic virus type 1 in the general population is
 
unknown. AIDS Rev 2009; 11:205-214.
 
7. Morofuji-Hirata M, Kajiyama W, Nakashima K, Noguchi A, Hayashi
 
J,Kashiwagi S. Prevalence of antibody to human T-cell lymphotropic
 
virus type I in Okinawa, Japan, after an interval of 9 years.
 
Am J Epidemiol 1993; 137:43-48.
 
8. Hinuma Y, Komoda H, Chosa T, Kondo T, Kohakura M, Takenaka
 
T
 
 
, et al.
Antibodies to adult T-cell leukemia-virus-associated antigen
(ATLA) in sera from patients with ATL and controls in Japan:
 
a nation-wide sero-epidemiologic study. Int J Cancer 1982; 29:631-
 
635.
 
9. Blattner WA, Kalyanaraman VS, Robert-Guroff M, Lister TA, Galton
 
DA, Sarin PS
 
 
, et al.
The human type-C retrovirus, HTLV, in
Blacks from the Caribbean region, and relationship to adult Tcell
 
leukemia/lymphoma. Int J Cancer 1982; 30:257-264.
 
10. Reeves WC, Saxinger C, Brenes MM, Quiroz E, Clark JW, Hoh MW
 
 
 
,
et al.
 
 
 
Human T-cell lymphotropic virus type I (HTLV-I) seroepidemiology
and risk factors in metropolitan Panama. Am J Epidemiol
 
1988; 127:532-539.
 
11. Maloney EM, Ramirez H, Levin A,Blattner WA. A survey of the human
 
T-cell lymphotropic virus type I (HTLV-I) in south-western
 
Colombia. Int J Cancer 1989; 44:419-423.
 
12. Rafatpanah H, Hedayati-Moghaddam MR, Fathimoghadam F,
 
Bidkhori HR, Shamsian SK, Ahmadi S
 
 
, et al.
High prevalence of
HTLV-I infection in Mashhad, Northeast Iran: a population-based
 
seroepidemiology survey. J Clin Virol 2011; 52:172-176.
 
13. Azarpazhooh MR, Hasanpour K, Ghanbari M, Rezaee SA, Mashkani
 
B, Hedayati-Moghaddam MR
 
 
, et al.
Human T-Lymphotropic
Virus Type 1 Prevalence in Northeastern Iran, Sabzevar: An Epidemiologic-
 
Based Study and Phylogenetic Analysis. AIDS Res Hum
 
Retroviruses 2012;
 
14. Tarhini M, Kchour G, Zanjani DS, Rafatpanah H, Otrock ZK, Bazarbachi
 
A
 
 
, et al.
Declining tendency of human T-cell leukaemia
virus type I carrier rates among blood donors in Mashhad, Iran.
 
Pathology 2009; 41:498-499.
 
15. Rafatpanah H, Farid R, Golanbar G,Jabbari Azad F. HTLV-I Infection:
 
virus structure, immune response to the virus and genetic
 
association studies in HTLV-I-infected individuals. Iran J Allergy
 
Asthma Immunol 2006; 5:153-166.
 
16. Bangham CR,Osame M. Cellular immune response to HTLV-I. Oncogene
 
2005; 24:6035-6046.
 
17. Furukawa Y, Yamashita M, Usuku K, Izumo S, Nakagawa M,Osame
 
M. Phylogenetic subgroups of human T cell lymphotropic virus
 
(HTLV) type I in the tax gene and their association with different
 
risks for HTLV-I-associated myelopathy/tropical spastic paraparesis.
 
J Infect Dis 2000; 182:1343-1349.
 
18. Daenke S, Nightingale S, Cruickshank JK,Bangham CR. Sequence
 
variants of human T-cell lymphotropic virus type I from patients
 
with tropical spastic paraparesis and adult T-cell leukemia do
 
not distinguish neurological from leukemic isolates. J Virol
 
1990; 64:1278-1282.
 
 
207
Immunopathogenecity of HTLV-I in HAM/TSP Rafatpanah H et al
Iran J Basic Med Sci; Vol. 16, No. 3, Mar 2013
19. Mahieux R, de The G,Gessain A. The tax mutation at nucleotide
7959 of human T-cell leukemia virus type 1 (HTLV-I) is not associated
with tropical spastic paraparesis/HTLV-I-associated myelopathy
but is linked to the cosmopolitan molecular genotype.
J Virol 1995; 69:5925-5927.
20. Richardson JH, Edwards AJ, Cruickshank JK, Rudge P,Dalgleish
AG.
In vivo
cellular tropism of human T-cell leukemia virus type 1.
J Virol 1990; 64:5682-5687.
 
21. Koyanagi Y, Itoyama Y, Nakamura N, Takamatsu K, Kira J, Iwamasa
 
T
 
 
, et al. In vivo
infection of human T-cell leukemia virus type I in
non-T cells. Virology 1993; 196:25-33.
 
22. Hanon E, Stinchcombe JC, Saito M, Asquith BE, Taylor GP, Tanaka
 
Y
 
 
, et al.
Fratricide among CD8(+) T lymphocytes naturally infected
with human T cell lymphotropic virus type I. Immunity 2000;
 
13:657-664.
 
23. Cho I, Sugimoto M, Mita S, Tokunaga M, Imamura F,Ando M.
 
 
 
In
vivo
 
 
 
proviral burden and viral RNA expression in T cell subsets of
patients with human T lymphotropic virus type-1-associated myelopathy/
 
tropical spastic paraparesis. Am J Trop Med Hyg 1995;
 
53:412-418.
 
24. Koralnik IJ, Lemp JF, Jr., Gallo RC,Franchini G.
 
 
In vitro
infection of
human macrophages by human T-cell leukemia/lymphotropic
 
virus type I (HTLV-I). AIDS Res Hum Retroviruses 1992; 8:1845-
 
1849.
 
25. de Revel T, Mabondzo A, Gras G, Delord B, Roques P, Boussin F
 
 
 
, et
al. In vitro
 
 
 
infection of human macrophages with human T-cell
leukemia virus type 1. Blood 1993; 81:1598-1606.
 
26. Macatonia SE, Cruickshank JK, Rudge P,Knight SC. Dendritic cells
 
from patients with tropical spastic paraparesis are infected with
 
HTLV-I and stimulate autologous lymphocyte proliferation. AIDS
 
Res Hum Retroviruses 1992; 8:1699-1706.
 
27. Hishizawa M, Imada K, Kitawaki T, Ueda M, Kadowaki N,Uchiyama
 
T. Depletion and impaired interferon-alpha-producing capacity
 
of blood plasmacytoid dendritic cells in human T-cell leukaemia
 
virus type I-infected individuals. Br J Haematol 2004; 125:568-575.
 
28. Jones KS, Petrow-Sadowski C, Huang YK, Bertolette DC,Ruscetti
 
FW. Cell-free HTLV-I infects dendritic cells leading to transmission
 
and transformation of CD4(+) T cells. Nat Med 2008; 14:429-
 
436.
 
29. Journo C,Mahieux R. HTLV-I and innate immunity. Viruses 2011;
 
3:1374-1394.
 
30. Jain P, Manuel SL, Khan ZK, Ahuja J, Quann K,Wigdahl B. DCSIGN
 
mediates cell-free infection and transmission of human
 
T-cell lymphotropic virus type 1 by dendritic cells. J Virol 2009;
 
83:10908-10921.
 
31. Oliere S, Douville R, Sze A, Belgnaoui SM,Hiscott J. Modulation of
 
innate immune responses during human T-cell leukemia virus
 
(HTLV-I) pathogenesis. Cytokine Growth Factor Rev 2011; 22:197-
 
210.
 
32. Vivier E, Tomasello E, Baratin M, Walzer T,Ugolini S. Functions of
 
natural killer cells. Nat Immunol 2008; 9:503-510.
 
33. Fujihara K, Itoyama Y, Yu F, Kubo C,Goto I. Cellular immune surveillance
 
against HTLV-I infected T lymphocytes in HTLV-I associated
 
myelopathy/tropical spastic paraparesis (HAM/TSP). J Neurol
 
Sci 1991; 105:99-107.
 
34. Yu F, Itoyama Y, Fujihara K,Goto I. Natural killer (NK) cells in
 
HTLV-I-associated myelopathy/tropical spastic paraparesis-decrease
 
in NK cell subset populations and activity in HTLV-I seropositive
 
individuals. J Neuroimmunol 1991; 33:121-128.
 
35. Saito M, Braud VM, Goon P, Hanon E, Taylor GP, Saito A
 
 
, et al.
Low
frequency of CD94/NKG2A+ T lymphocytes in patients with
 
HTLV-I-associated myelopathy/tropical spastic paraparesis, but
 
not in asymptomatic carriers. Blood 2003; 102:577-584.
 
36. Vine AM, Heaps AG, Kaftantzi L, Mosley A, Asquith B, Witkover A
 
 
 
,
et al.
 
 
 
The role of CTLs in persistent viral infection: cytolytic gene
expression in CD8+ lymphocytes distinguishes between individuals
 
with a high or low proviral load of human T cell lymphotropic
 
virus type 1. J Immunol 2004; 173:5121-5129.
 
37. Norris PJ, Hirschkorn DF, DeVita DA, Lee TH,Murphy EL. Human T
 
cell leukemia virus type 1 infection drives spontaneous proliferation
 
of natural killer cells. Virulence 2010; 1:19-28.
 
38. Azakami K, Sato T, Araya N, Utsunomiya A, Kubota R, Suzuki K
 
 
 
,
et al.
 
 
 
Severe loss of invariant NKT cells exhibiting anti-HTLV-I activity
in patients with HTLV-I-associated disorders. Blood 2009;
 
114:3208-3215.
 
39. Ndhlovu LC, Snyder-Cappione JE, Carvalho KI, Leal FE, Loo CP,
 
Bruno FR
 
 
, et al.
Lower numbers of circulating Natural Killer T (NK
T) cells in individuals with human T lymphotropic virus type 1
 
(HTLV-I) associated neurological disease. Clin Exp Immunol
 
2009; 158:294-299.
 
40. Manns A, Hisada M,La Grenade L. Human T-lymphotropic virus
 
type I infection. Lancet 1999; 353:1951-1958.
 
41. Bangham CR. The immune response to HTLV-I. Curr Opin Immunol
 
2000; 12:397-402.
 
42. Manns A, Murphy EL, Wilks R, Haynes G, Figueroa JP, Hanchard
 
B
 
 
, et al.
Detection of early human T-cell lymphotropic virus type
I antibody patterns during seroconversion among transfusion
 
recipients. Blood 1991; 77:896-905.
 
43. Nagasato K, Nakamura T, Shirabe S, Shibayama K, Ohishi K, Ichinose
 
K
 
 
, et al.
Presence of serum anti-human T-lymphotropic virus
type I (HTLV-I) IgM antibodies means persistent active replication
 
of HTLV-I in HTLV-I-associated myelopathy. J Neurol Sci 1991;
 
103:203-208.
 
44. Kira J, Nakamura M, Sawada T, Koyanagi Y, Ohori N, Itoyama Y
 
 
 
, et
al.
 
 
 
Antibody titers to HTLV-I-p40tax protein and gag-env hybrid
protein in HTLV-I-associated myelopathy/tropical spastic paraparesis:
 
correlation with increased HTLV-I proviral DNA load. J
 
Neurol Sci 1992; 107:98-104.
 
45. Grimaldi LM, Roos RP, Devare SG, Casey JM, Maruo Y, Hamada T
 
 
 
,
et al.
 
 
 
HTLV-I-associated myelopathy: oligoclonal immunoglobulin
G bands contain anti-HTLV-I p24 antibody. Ann Neurol 1988;
 
24:727-731.
 
46. Yoshida M, Osame M, Kawai H, Toita M, Kuwasaki N, Nishida Y
 
 
 
, et
al.
 
 
 
Increased replication of HTLV-I in HTLV-I-associated myelopathy.
Ann Neurol 1989; 26:331-335.
 
47. Kira J, Koyanagi Y, Yamada T, Itoyama Y, Goto I, Yamamoto N
 
 
 
, et al.
 
Increased HTLV-I proviral DNA in HTLV-I-associated myelopathy:
a quantitative polymerase chain reaction study. Ann Neurol 1991;
29:194-201.
48. Gessain A, Saal F, Gout O, Daniel MT, Flandrin G, de The G
 
, et al.
 
High human T-cell lymphotropic virus type I proviral DNA load
with polyclonal integration in peripheral blood mononuclear
cells of French West Indian, Guianese, and African patients with
tropical spastic paraparesis. Blood 1990; 75:428-433.
49. Kubota R, Fujiyoshi T, Izumo S, Yashiki S, Maruyama I, Osame
M
, et al.
Fluctuation of HTLV-I proviral DNA in peripheral blood
mononuclear cells of HTLV-I-associated myelopathy. J Neuroimmunol
 
1993; 42:147-154.
 
50. Kirk PD, Witkover A, Courtney A, Lewin AM, Wait R, Stumpf MP
 
 
 
,
et al.
 
 
 
Plasma proteome analysis in HTLV-I-associated myelopathy/
tropical spastic paraparesis. Retrovirology 2011; 8:81.
 
51. Abbas AK, Lichtman AH,Pober JS. Effector mechanisms of T cellmediated
 
immune reactions. In: Abbas AK, Lichtman AH and
 
Pober JS, editors. Cellular and Molecular Immunology. 3rd ed.
 
Philadelphia, PA: Saunders; 1997. p. 278-296.
 
52. Jacobson S, Shida H, McFarlin DE, Fauci AS,Koenig S. Circulating
 
CD8+ cytotoxic T lymphocytes specific for HTLV-I pX in patients
 
with HTLV-I associated neurological disease. Nature 1990;
 
348:245-248.
 
53. Jacobson S, Reuben JS, Streilein RD,Palker TJ. Induction of CD4+,
 
human T lymphotropic virus type-1-specific cytotoxic T lymphocytes
 
from patients with HAM/TSP. Recognition of an immunogenic
 
region of the gp46 envelope glycoprotein of human T lymphotropic
 
virus type-1. J Immunol 1991; 146:1155-1162.
 
54. Elovaara I, Koenig S, Brewah AY, Woods RM, Lehky T,Jacobson S.
 
High human T cell lymphotropic virus type 1 (HTLV-I)-specific
 
precursor cytotoxic T lymphocyte frequencies in patients with
 
HTLV-I-associated neurological disease. J Exp Med 1993; 177:1567-
 
1573.
 
55. Parker CE, Daenke S, Nightingale S,Bangham CR. Activated, HTLVI-
 
specific cytotoxic T-lymphocytes are found in healthy seropositives
 
as well as in patients with tropical spastic paraparesis. Vi
 
 
 
208
 
Rafatpanah H et al Immunopathogenecity of HTLV-I in HAM/TSP
Iran J Basic Med Sci; Vol. 16, No. 3, Mar 2013
rology 1992; 188:628-636.
56. Kannagi M, Harada S, Maruyama I, Inoko H, Igarashi H, Kuwashima
G
, et al.
Predominant recognition of human T cell leukemia
virus type I (HTLV-I) pX gene products by human CD8+ cytotoxic
 
T cells directed against HTLV-I-infected cells. Int Immunol 1991;
 
3:761-767.
 
57. Daenke S, Kermode AG, Hall SE, Taylor G, Weber J, Nightingale
 
S
 
 
, et al.
High activated and memory cytotoxic T-cell responses
to HTLV-I in healthy carriers and patients with tropical spastic
 
paraparesis. Virology 1996; 217:139-146.
 
58. Greten TF, Slansky JE, Kubota R, Soldan SS, Jaffee EM, Leist TP
 
 
 
, et
al.
 
 
 
Direct visualization of antigen-specific T cells: HTLV-I Tax11-
19- specific CD8(+) T cells are activated in peripheral blood and
 
accumulate in cerebrospinal fluid from HAM/TSP patients. Proc
 
Natl Acad Sci U S A 1998; 95:7568-7573.
 
59. Bieganowska K, Hollsberg P, Buckle GJ, Lim DG, Greten TF, Schneck
 
J
 
 
, et al.
Direct analysis of viral-specific CD8+ T cells with soluble
HLA-A2/Tax11-19 tetramer complexes in patients with human
 
T cell lymphotropic virus-associated myelopathy. J Immunol
 
1999; 162:1765-1771.
 
60. Nagai M, Kubota R, Greten TF, Schneck JP, Leist TP,Jacobson S. Increased
 
activated human T cell lymphotropic virus type I (HTLVI)
 
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 2001; 183:197-
 
205.
 
61. Biddison WE, Kubota R, Kawanishi T, Taub DD, Cruikshank WW,
 
Centre DM
 
 
, et al.
Human T cell leukemia virus type I (HTLV-I)-specific
CD8+ CTL clones from patients with HTLV-I-associated neurologic
 
disease secrete proinflammatory cytokines, chemokines,
 
and matrix metalloproteinase. J Immunol 1997; 159:2018-2025.
 
62. Kubota R, Kawanishi T, Matsubara H, Manns A,Jacobson S. Demonstration
 
of human T lymphotropic virus type I (HTLV-I) taxspecific
 
CD8+ lymphocytes directly in peripheral blood of HTLVI-
 
associated myelopathy/tropical spastic paraparesis patients by
 
intracellular cytokine detection. J Immunol 1998; 161:482-488.
 
63. Kubota R, Kawanishi T, Matsubara H, Manns A,Jacobson S. HTLV-I
 
specific IFN-gamma+ CD8+ lymphocytes correlate with the proviral
 
load in peripheral blood of infected individuals. J Neuroimmunol
 
2000; 102:208-215.
 
64. Saito M. Immunogenetics and the Pathological Mechanisms
 
of Human T-Cell Leukemia VirusType 1- (HTLV-I-)Associated Myelopathy/
 
Tropical Spastic Paraparesis (HAM/TSP). Interdiscip Perspect
 
Infect Dis 2010; 2010:478461.
 
65. Goon PK, Hanon E, Igakura T, Tanaka Y, Weber JN, Taylor GP
 
 
 
, et al.
 
High frequencies of Th1-type CD4(+) T cells specific to HTLV-I Env
and Tax proteins in patients with HTLV-I-associated myelopathy/
tropical spastic paraparesis. Blood 2002; 99:3335-3341.
66. Kitze B, Usuku K, Yamano Y, Yashiki S, Nakamura M, Fujiyoshi T
 
,
et al.
 
 
 
Human CD4+ T lymphocytes recognize a highly conserved
epitope of human T lymphotropic virus type 1 (HTLV-I) env gp21
 
restricted by HLA DRB1*0101. Clin Exp Immunol 1998; 111:278-285.
 
67. Goon PK, Igakura T, Hanon E, Mosley AJ, Barfield A, Barnard AL
 
 
 
, et
al.
 
 
 
Human T cell lymphotropic virus type I (HTLV-I)-specific CD4+
T cells: immunodominance hierarchy and preferential infection
 
with HTLV-I. J Immunol 2004; 172:1735-1743.
 
68. Bangham CR. The immune control and cell-to-cell spread of human
 
T-lymphotropic virus type 1. J Gen Virol 2003; 84:3177-3189.
 
69. Goon PK, Igakura T, Hanon E, Mosley AJ, Asquith B, Gould KG
 
 
 
, et
al.
 
 
 
High circulating frequencies of tumor necrosis factor alphaand
interleukin-2-secreting human T-lymphotropic virus type 1
 
(HTLV-I)-specific CD4+ T cells in patients with HTLV-I-associated
 
neurological disease. J Virol 2003; 77:9716-9722.
 
70. Sabouri AH, Saito M, Usuku K, Bajestan SN, Mahmoudi M, Forughipour
 
M
 
 
, et al.
Differences in viral and host genetic risk factors for
development of human T-cell lymphotropic virus type 1 (HTLV-I)-
 
associated myelopathy/tropical spastic paraparesis between Iranian
 
and Japanese HTLV-I-infected individuals. J Gen Virol 2005;
 
86:773-781.
 
71. Jeffery KJ, Siddiqui AA, Bunce M, Lloyd AL, Vine AM, Witkover AD
 
 
 
,
et al.
 
 
 
The influence of HLA class I alleles and heterozygosity on
the outcome of human T cell lymphotropic virus type I infection.
 
J Immunol 2000; 165:7278-7284.
 
72. Jeffery KJ, Usuku K, Hall SE, Matsumoto W, Taylor GP, Procter J
 
 
 
, et
al.
 
 
 
HLA alleles determine human T-lymphotropic virus-I (HTLV-I)
proviral load and the risk of HTLV-I-associated myelopathy. Proc
 
Natl Acad Sci U S A 1999; 96:3848-3853.
 
73. Rafatpanah H, Pravica V, Faridhosseini R, Tabatabaei A, Ollier
 
W, Poulton K
 
 
, et al.
Association between HLA-DRB1*01 and HLACw*
08 and outcome following HTLV-I infection. Iran J Immunol
 
2007; 4:94-100.
 
74. Tendler CL, Greenberg SJ, Burton JD, Danielpour D, Kim SJ,
 
Blattner WA
 
 
, et al.
Cytokine induction in HTLV-I associated myelopathy
and adult T-cell leukemia: alternate molecular mechanisms
 
underlying retroviral pathogenesis. J Cell Biochem 1991;
 
46:302-311.
 
75. Hanon E, Goon P, Taylor GP, Hasegawa H, Tanaka Y, Weber JN
 
 
 
, et
al.
 
 
 
High production of interferon gamma but not interleukin-2
by human T-lymphotropic virus type I-infected peripheral blood
 
mononuclear cells. Blood 2001; 98:721-726.
 
76. Fontenot JD, Gavin MA,Rudensky AY. Foxp3 programs the development
 
and function of CD4+CD25+ regulatory T cells. Nat Immunol
 
2003; 4:330-336.
 
77. Hori S, Nomura T,Sakaguchi S. Control of regulatory T cell development
 
by the transcription factor Foxp3. Science 2003;
 
299:1057-1061.
 
78. Yamano Y, Takenouchi N, Li HC, Tomaru U, Yao K, Grant CW
 
 
 
, et al.
 
Virus-induced dysfunction of CD4+CD25+ T cells in patients with
HTLV-I-associated neuroimmunological disease. J Clin Invest
2005; 115:1361-1368.
79. Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z
 
, et al.
 
Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant selftolerance
and autoimmune disease. Immunol Rev 2006; 212:8-27.
80. Oh U, Grant C, Griffith C, Fugo K, Takenouchi N,Jacobson S. Reduced
Foxp3 protein expression is associated with inflammatory
disease during human t lymphotropic virus type 1 Infection. J Infect
Dis 2006; 193:1557-1566.
81. Hayashi D, Kubota R, Takenouchi N, Tanaka Y, Hirano R, Takashima
H
, et al.
Reduced Foxp3 expression with increased cytomegalovirus-
specific CTL in HTLV-I-associated myelopathy. J Neuroimmunol
 
2008; 200:115-124.
 
82. Toulza F, Heaps A, Tanaka Y, Taylor GP,Bangham CR. High frequency
 
of CD4+FoxP3+ cells in HTLV-I infection: inverse correlation
 
with HTLV-I-specific CTL response. Blood 2008; 111:5047-5053.
 
83. Best I, Lopez G, Verdonck K, Gonzalez E, Tipismana M, Gotuzzo
 
E
 
 
, et al.
IFN-gamma production in response to Tax 161-233, and
frequency of CD4+ Foxp3+ and Lin HLA-DRhigh CD123+ cells, discriminate
 
HAM/TSP patients from asymptomatic HTLV-I-carriers
 
in a Peruvian population. Immunology 2009; 128:e777-786.
 
84. Araya N, Sato T, Yagishita N, Ando H, Utsunomiya A, Jacobson S
 
 
 
,
et al.
 
 
 
Human T-lymphotropic virus type 1 (HTLV-I) and regulatory
T cells in HTLV-I-associated neuroinflammatory disease. Viruses
 
2011; 3:1532-1548.
 
85. Ramirez JM, Brembilla NC, Sorg O, Chicheportiche R, Matthes T,
 
Dayer JM
 
 
, et al.
Activation of the aryl hydrocarbon receptor reveals
distinct requirements for IL-22 and IL-17 production by human
 
T helper cells. Eur J Immunol 2010; 40:2450-2459.
 
86. Yoshie O, Fujisawa R, Nakayama T, Harasawa H, Tago H, Izawa D
 
 
 
, et
al.
 
 
 
Frequent expression of CCR4 in adult T-cell leukemia and human
T-cell leukemia virus type 1-transformed T cells. Blood 2002;
 
99:1505-1511.
 
87. Yamano Y, Araya N, Sato T, Utsunomiya A, Azakami K, Hasegawa
 
D
 
 
, et al.
Abnormally high levels of virus-infected IFN-gamma+
CCR4+ CD4+ CD25+ T cells in a retrovirus-associated neuroinflammatory
 
disorder. PLoS One 2009; 4:e6517.
 
88. Yoshie O. Expression of CCR4 in adult T-cell leukemia. Leuk Lymphoma
 
2005; 46:185-190.