Retrovirally induced CTL degranulation mediated by IL-15 expression and infection of mononuclear phagocytes in patients with HTLV-I-associated neurologic disease.
CD8(+) T cells contribute to central nervous system inflammation in human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We analyzed CD8(+) T-cell dysfunction (degranulation and IFN-gamma production) and have demonstrated that CD8(+) T cells of patients with HAM/TSP (HAM/TSP patients) spontaneously degranulate and express IFN-gamma in ex vivo unstimulated culture. CD8(+) T cells of HTLV-I asymptomatic carriers and healthy donors did not. Spontaneous degranulation was detected in Tax11-19/HLA-A*201 tetramer(+) cells, but not in CMV pp65 tetramer(+) cells. Interestingly, degranulation and IFN-gamma production in CD8(+) T cells was induced by coculture with autologous CD14(+) cells, but not CD4(+) T cells, of HAM/TSP patients, which correlated with proviral DNA load in CD14(+) cells of infected patients. Moreover, the expression of IL-15, which induced degranulation and IFN-gamma production in infected patients, was enhanced on surface of CD14(+) cells in HAM/TSP patients. Blockade of MHC class I and IL-15 confirmed these results. Thus, CD8(+) T-cell dysregulation was mediated by both virus infection and enhanced IL-15 on CD14(+) cells in HAM/TSP patients. Despite lower viral expression than in CD4(+) T cells, HTLV-I-infected or -activated CD14(+) cells may be a heretofore important but under recognized reservoir particularly in HAM/TSP patients.
Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Yoshimi
Y
Enose-Akahata
Unsong
U
Oh
Christian
C
Grant
Steven
S
Jacobson
D018414:CD8-Positive T-Lymphocytes / Q000821:virology; D015550:Cell Degranulation; D018920:Coculture Techniques; D015870:Gene Expression / Q000276:immunology; D015490:HTLV-I Infections; D015368:Human T-lymphotropic virus 1 / Q000472:pathogenicity*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D019409:Interleukin-15 / Q000235:genetics*; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D015493:Paraparesis, Tropical Spastic / Q000821:virology*; D010586:Phagocytes / Q000821:virology*; D013602:T-Lymphocytes, Cytotoxic / Q000821:virology*
D019409:Interleukin-15; D018950:Lipopolysaccharide Receptors; D007371:Interferon-gamma