Functional impairment of Tax-specific but not cytomegalovirus-specific CD8+ T lymphocytes in a minor population of asymptomatic human T-cell leukemia virus type 1-carriers

<p>Abstract</p> <p>Background</p> <p>Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a small percentage of infected individuals. ATL is often associated with general immune suppression and an impaired HTLV-1-specific T-cell response, an important host defense system. We previously found that a small fraction of asymptomatic HTLV-1-carriers (AC) already showed impaired T-cell responses against the major target antigen, Tax. However, it is unclear whether the impaired HTLV-1 Tax-specific T-cell response in these individuals is an HTLV-1-specific phenomenon, or merely reflects general immune suppression. In this study, in order to characterize the impaired HTLV-1-specific T-cell response, we investigated the function of Tax-specific CD8⁺T-cells in various clinical status of HTLV-1 infection.</p> <p>Results</p> <p>By using tetramers consisting of HLA-A*0201, -A*2402, or -A*1101, and corresponding Tax epitope peptides, we detected Tax-specific CD8⁺T-cells in the peripheral blood from 87.0% of ACs (n = 20/23) and 100% of HAM/TSP patients (n = 18/18) tested. We also detected Tax-specific CD8⁺T-cells in 38.1% of chronic type ATL (cATL) patients (n = 8/21), although its frequencies in peripheral blood CD8⁺T cells were significantly lower than those of ACs or HAM/TSP patients. Tax-specific CD8⁺T-cells detected in HAM/TSP patients proliferated well in culture and produced IFN-γ when stimulated with Tax peptides. However, such functions were severely impaired in the Tax-specific CD8⁺T-cells detected in cATL patients. In ACs, the responses of Tax-specific CD8⁺T-cells were retained in most cases. However, we found one AC sample whose Tax-specific CD8⁺T-cells hardly produced IFN-γ, and failed to proliferate and express activation (CD69) and degranulation (CD107a) markers in response to Tax peptide. Importantly, the same AC sample contained cytomegalovirus (CMV) pp65-specific CD8⁺T-cells that possessed functions upon CMV pp65 peptide stimulation. We further examined additional samples of two smoldering type ATL patients and found that they also showed dysfunctions of Tax-specific but not CMV-specific CD8⁺T-cells.</p> <p>Conclusions</p> <p>These findings indicated that Tax-specific CD8⁺T-cells were scarce and dysfunctional not only in ATL patients but also in a limited AC population, and that the dysfunction was selective for HTLV-1-specifc CD8⁺T-cells in early stages.</p

Identification of the human eosinophil lineage-committed progenitor: revision of phenotypic definition of the human common myeloid progenitor

To establish effective therapeutic strategies for eosinophil-related disorders, it is critical to understand the developmental pathway of human eosinophils. In mouse hematopoiesis, eosinophils originate from the eosinophil lineage-committed progenitor (EoP) that has been purified downstream of the granulocyte/macrophage progenitor (GMP). We show that the EoP is also isolatable in human adult bone marrow. The previously defined human common myeloid progenitor (hCMP) population (Manz, M.G., T. Miyamoto, K. Akashi, and I.L. Weissman. 2002. Proc. Natl. Acad. Sci. USA. 99:11872–11877) was composed of the interleukin 5 receptor α chain+ (IL-5Rα+) and IL-5Rα− fractions, and the former was the hEoP. The IL-5Rα+CD34+CD38+IL-3Rα+CD45RA− hEoPs gave rise exclusively to pure eosinophil colonies but never differentiated into basophils or neutrophils. The IL-5Rα− hCMP generated the hEoP together with the hGMP or the human megakaryocyte/erythrocyte progenitor (hMEP), whereas hGMPs or hMEPs never differentiated into eosinophils. Importantly, the number of hEoPs increased up to 20% of the conventional hCMP population in the bone marrow of patients with eosinophilia, suggesting that the hEoP stage is involved in eosinophil differentiation and expansion in vivo. Accordingly, the phenotypic definition of hCMP should be revised to exclude the hEoP; an “IL-5Rα–negative” criterion should be added to define more homogenous hCMP. The newly identified hEoP is a powerful tool in studying pathogenesis of eosinophilia and could be a therapeutic target for a variety of eosinophil-related disorders

Etiological factors in primary hepatic B-cell lymphoma

Sixty-four cases of malignant lymphoma involving the liver were examined. Of these, 20 cases were histologically confirmed to be primary hepatic B-cell lymphoma. Twelve of these 20 cases were diffuse large B-cell lymphoma (DLBCL) and eight cases were mucosa-associated lymphoid tissue (MALT) lymphoma. Of the 12 cases of DLBCL, six were immunohistologically positive for CD10 and/or Bcl6 (indicating a germinal center phenotype), six were positive for Bcl2, and five were positive for CD25. Eight of the 12 DLBCL cases (66.7%) and two of the eight MALT lymphoma cases (25%) had serum anti-hepatitis C virus (HCV) antibodies and HCV RNA. The incidence of HCV infection was significantly higher in the hepatic DLBCL cases than in systemic intravascular large B-cell cases with liver involvement (one of 11 cases, 9.1%) and T/NK-cell lymphoma cases (one of 19 cases, 5.3%) (p < 0.01 for both). Two hepatic DLBCL cases (16.7%) had rheumatoid arthritis treated with methotrexate, and four MALT lymphoma cases (50%) had Sjögren’s syndrome, primary biliary cirrhosis, or autoimmune hepatitis; one case in each of these two groups was complicated by chronic HCV-seropositive hepatitis. Although primary hepatic lymphoma is rare, persistent inflammatory processes associated with HCV infection or autoimmune disease may play independent roles in the lymphomagenesis of hepatic B cells