Abnormally high levels of virus-infected IFN-gamma+ CCR4+ CD4+ CD25+ T cells in a retrovirus-associated neuroinflammatory disorder.
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.


RESULTS
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-gamma 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-gamma-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-gamma(+)CCR4(+)CD4(+)CD25(+) T cells--that is abnormally increased and functionally altered in this retrovirus-associated inflammatory disorder of the central nervous system.
Yamano
Yoshihisa
Y
Department of Molecular Medical Science, Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Japan. yyamano@marianna-u.ac.jp
Araya
Natsumi
N
Sato
Tomoo
T
Utsunomiya
Atae
A
Azakami
Kazuko
K
Hasegawa
Daisuke
D
Izumi
Toshihiko
T
Fujita
Hidetoshi
H
Aratani
Satoko
S
Yagishita
Naoko
N
Fujii
Ryoji
R
Nishioka
Kusuki
K
Jacobson
Steven
S
Nakajima
Toshihiro
T
D015704:CD4 Antigens / Q000032:analysis*; D016022:Case-Control Studies; D049109:Cell Proliferation; D015490:HTLV-I Infections / Q000276:immunology / Q000821:virology*; D015368:Human T-lymphotropic virus 1 / Q000302:isolation & purification*; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis*; D015847:Interleukin-4 / Q000096:biosynthesis; D009422:Nervous System Diseases / Q000276:immunology / Q000821:virology*; D054398:Receptors, CCR4 / Q000032:analysis*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology*
D015704:CD4 Antigens; D053645:Interleukin-2 Receptor alpha Subunit; D054398:Receptors, CCR4; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma