Immunity and suppression in radiation- and radiation leukemia virus (RadLV)-induced leukemogenesis

Adult C57BL/6 (B6) mice exposed to fractionated irradiation or inoculated with a highly leukemogenic RadLV (A-RadLV) develop high incidence of lymphatic leukemias after a latency of 3-5 months. Inoculation of a low leukemogenic RadLV variant (D-RadLV) does not result in lymphoma development unless the animals receive a single, sublethal dose of irradiation. Whereas virus-induced primary lymphomas produce virus, express gp70 and are all immunogenic, those induced by X-rays are devoid of virus expression and are not immunogenic. A-RadLV inoculation into B6 mice is associated with early induction of virus specific, cyclophosphamide sensitive suppressor T cells which are capable of abrogating a potential antitumor immune responsiveness. D-RadLV, on the other hand, induces reactive T lymphocytes that arrest leukemogenesis unless their function is impaired by irradiation. In (B6 X BALB/c)F1 mice both A-RadLV and D-RadLV leukemogenesis depend on sublethal irradiation of the host, and both induce reactive T cells. These results suggest that (a) RadLV and X-ray induced leukemogeneses involve different etiologies. (b) Different leukemogenic treatments evoke different host responses early in latency which can either sustain or interfere with lymphoma progression.     

Development of EBV-positive T-cell lymphoma following infection of peripheral blood T cells with EBV.

Chronic active Epstein-Barr virus (EBV) infection is manifested clinically by the persistence of infectious mononucleosis-like symptoms or its complications for a prolonged period ranging from one to several years. This syndrome may include severe disease manifestations and can be fatal. The role of EBV in the pathogenesis of chronic active EBV infection has been unclear. We investigated two Japanese patients with severe chronic active EBV infection who subsequently developed EBV-positive T-cell lymphoma. We found that the patients had evidence of EBV infection in the peripheral blood CD4+ T-cells 19 and 3 months, respectively, before the T-cell lymphoma was diagnosed. The lymphomas were infected with monoclonal EBV and expressed the EBV latency genes EBNA-1, LMP-1, and LMP-2A, a virus latency pattern referred to as latency II. Genetic studies showed that the virus detected in the T-cell lymphoma was indistinguishable from the virus in the peripheral blood CD4+ T-cells. These studies support an important pathogenetic role of T-cell infection with EBV in chronic active EBV infection and in the EBV-positive T-cell lymphoma that followed.     

High- and low-leukemogenic variants of the radiation leukemia virus (RadLV): Immunogenic,suppressive and genetic properties in relation to leukemogenic activity

C57BL/6 (B6) mice inoculated with the highly leukemogenic variant of the radiation leukemia virus (A-RadLV) develop suppressor cells capable of abrogating potential anti-tumor immunity in vitro and in vivo, Inoculation of B6 animals with the low-leukemogenic D-RadLV variant does not result in suppressor cell generation but induces antitumor reactive lymphocytes. A-RadLV and D-RadLV are not leukemogenic in BALB/c or (B6 × BALB/c)F₁ (F₁) mice, and reactive but not suppressor lymphocytes could be demonstrated in F₁ animals inoculated with either virus. Infectivity assays and fingerprint analysis revealed that A-RadLV and D-RadLV contain viruses with N and B tropism. In addition, thymoma cells induced by A-RadLV produced another virus with a fingerprint pattern containing X-MuLV elements. The possible implications of the different virus types on the immunogenic and leukemogenic properties of the RadLV variants are discussed.     

Augmented expression of programmed death-1 in both neoplastic and non-neoplastic CD4+ T-cells in adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (ATL) is a CD4(+)CD25(+) T-cell malignancy infected with human T-cell leukemia virus type-I (HTLV-I). HTLV-I infection causes the T-cell dysfunction, which contributes to the immunodeficient state of the patients. Programmed death-1 (PD-1) can negatively regulate T-cell response, when its ligand, PD-L1 or PD-L2 mainly expressed on antigen presenting cells, binds to this B7 family receptor. We investigated whether PD-1 is expressed on CD4(+) neoplastic (and/or non-neoplastic) cells or CD8(+) cytotoxic cells in peripheral blood mononuclear cells from 11 patients with ATL. By flow cytometry, we found that the levels of PD-1 expression on both CD4(+)CD25(+) and CD4(+)CD25(-) T-cell populations were increased in ATL patients compared to normal healthy volunteers, while PD-1 levels on CD8(+) T-cells were comparable between the patients and normal subjects. In stimulation with anti-CD3 antibody, the proliferation of PD-1-expressing T-cells from ATL patients was weak when compared to that of PD-1-nonexpressing normal T-cells. In addition to PD-1, PD-L1 was coexpressed on ATL cells in some patients, and PD-L1 expression was enhanced by stimulation with anti-CD3 antibody. Finally, the production of cytokines such as TNF-alpha by ATL cells was restored by blockade of PD-1/PD-L1 interaction. These findings suggest that CD4(+) T-cells are the main PD-1-expressing cells rather than CD8(+) T-cells in ATL patients, and both neoplastic and normal CD4(+) cells are exhausted as a result of PD-1 expression, and additionally PD-L1 expression on the neoplastic cell.     

Atopic dermatitis-like non-erythrodermic leukemic variant of CD3(-/+dim) CD4(+) cutaneous T-cell lymphoma preceded by cutaneous papular xanthomatosis

We report a patient with cutaneous papular xanthomatosis who 4 years later developed a CD3(-/+dim)/CD4(+) T-cell lymphoma. Pruritic xerotic non-erythrodermic skin, eosinophilia and hyper-IgE were present and erroneously classified as atopic dermatitis. Flow cytometry and DNA ploidy analysis of both blood and skin lymphocytes, skin histology and blood T-cell receptor gene rearrangement studies confirmed diagnosis of T-cell lymphoma. Monoclonal CD3(-/+dim)/CD4(+) T-cells were especially prone to the synthesis of IL-13, a cytokine that is involved in IgE-secretion, and comprised both a medium (diploid) and large (hyperploid) sized T-cell populations with a similar immunophenotype. The majority of the normal residual T-cells were large granular lymphocytes, expressed activation-related and natural-killer-associated markers and secreted high levels of interferon gamma, suggesting that they might correspond to active cytotoxic cells directed against the neoplastic T-lymphocytes.     

High- and low-leukemogenic variants of the radiation leukemia virus (RadLV) differ in ability to induce tumor-specific immune suppression

Adult C57BL/6 mice inoculated intrathymically (i.t.) with the highly leukemogenic variant of the radiation leukemia virus (A-RadLV) develop suppressor cells capable of specifically abrogating a potential anti-tumor cytotoxic response in vitro. Suppressor cells were generated directly by the virus, independently of an initiation of a leukemogenic process. Inoculation of C57BL/6 animals with the low leukemogenic D-RadLV variant did not result in suppressor cell generation. It is proposed that induction of tumor-specific immune suppression by A-RadLV is essential for tumor progression, and the leukemogenic activity of D-RadLV is attributed to its inability to recruit suppressor cells.     

Geographic distribution of the incidence of adult T-cell leukemia/lymphoma and other malignancies in nagasaki prefecture,Japan

BACKGROUND: It remains unclear whether human T-cell lymphotropic virus type-I (HTLV-I) infection is associated with an increased risk of malignancies other than adult T-cell leukemia/lymphoma. METHODS: The authors investigated the geographic distribution of the incidence of adult T-cell leukemia/lymphoma and other malignancies in Nagasaki Prefecture, Japan, where HTLV-I is endemic. The world age-standardized incidence rates of adult T-cell leukemia/lymphoma and five cancers of other sites were calculated in 15 areas, using the data from the Nagasaki Prefectural Cancer Registry (1985-97). RESULTS: The incidence of adult T-cell leukemia/lymphoma was found to be positively correlated with that of biliary tract cancer in men (person-years-weighted r = 0.49, P = 0.06) and liver cancer in women (r = 0.56, P = 0.03), but not with cancer of the stomach, lung or cervix uteri. CONCLUSIONS: The results may not support the hypothesis that HTLV-I infection is strongly associated with an increased risk of cancer of the stomach, lung or cervix uteri. The association between HTLV-I infection and cancer of the biliary tract and the possible interaction between hepatitis C virus and HTLV-I in the development of liver cancer should be evaluated by prospective cohort studies.     

Characteristics of potential lymphoma-inducing cells in mice sensitive or resistant to lymphomagenesis by radiation leukemia virus variants

The relationship between the H-2-associated responsiveness of mice to radiation leukemia virus variants (A-RadLV and D-RadLV) lymphomagenesis and the characteristics of early occurring potential lymphoma-inducing cells (PLC) among thymus and bone marrow cells of these virus-infected mice was investigated. Sensitivity to virus-induced T-cell lymphomagenesis was shown to involve early occurrence of Thy-positive PLC, found predominantly among thymocytes, whereas resistance was rather related with early identification of PLC-Thy-negative cells mostly among bone marrow cells. PLC were further characterized in the sensitive (BL/6 + A-RadLV) and resistant (BL/6 + D-RadLV) situations by testing in parallel the tumorigenic potential (using the transplantation bioassay method) and type of thymus and bone marrow cell populations separated by different methods such as size fractionation by centrifugal elutriation, cytotoxic elimination of lymphocytes, or panning. The early occurring PLC among thymocytes of BL/6 mice 10-20 days following infection with A-RadLV were shown to be cortisone-resistant, Thy+, CD4+, and/or CD8+ medium size dividing thymocytes. PLC among thymocytes of BL/6 mice + D-RadLV, identified among the medium and large cell fractions, were shown to be cortisone-resistant Thy-, CD4-CD8- lymphocytes. High tumorigenic potential of PLC was demonstrated only among unseparated or separated (on size basis) bone marrow cells of BL/6 + D-RadLV (72-84%), whereas unseparated or separated fractions of bone marrow from BL/6 + A-RadLV had a low lymphomagenic potential (15-20%). The parallelism between the bone marrow fractions that induced optimal thymus cellularity following reconstitution of lethally irradiated mice and optimal lymphomagenicity stress the prothymocyte characteristics of PLC among bone marrow cells of BL/6 mice infected with D-RadLV. It is suggested that in resistant and sensitive haplotypes RadLV variants infect different cell populations and thereby induce PLC which differ in their capacity to present associative MuLV antigens with self H-2.     

Follicular T-cell lymphoma mimicking lymphocyte-rich classic Hodgkin lymphoma: a case report of a diagnostic pitfall

Follicular T-cell lymphoma (FTCL), one of the nodal T-cell lymphomas with T follicular helper (T_^FH) phenotype, is an uncommon disease. The diagnosis of FTCL is challenging on the distinction from the morphological mimics mostly exemplified by follicular lymphoma. Here, we described a case of FTCL that mimicked lymphocyte-rich classic Hodgkin lymphoma (LRCHL). A 47-year-old male presented with cervical lymphadenopathy. The biopsy specimen demonstrated nodular lymphoid proliferation, which included scattered CD30+ CD15- CD20- PAX5 weakly+ Hodgkin and Reed-Sternberg (HRS)-like cells and a rich distribution of CD3+ CD4+ PD1+ T-cells. Epstein Barr virus was not detected in HRS-like cells, but it was detected in a small proportion of the scattered lymphocytes. The large cells were also negative for programmed cell death ligand 1, which appeared to be coincidental as described in our previous report of LRCHL. However, flow cytometry showed a CD3- CD4+ T-cell population that constituted 37.4% of all gated lymphocytes. A PCR analysis showed a clonal T-cell receptor-gamma gene rearrangement, but not a clonal immunoglobulin heavy chain gene rearrangement, and showed RHOA G17V mutation. The constellation of these findings led us to revise the diagnosis to FTCL. This result indicated that our case belonged to a relatively indolent subgroup of nodal peripheral T-cell lymphoma of T_^FH phenotype, which affects patients ≤60 years old, recently proposed by our group. This case report expands our understanding of the morphologic spectrum of FTCL and its clinicopathologic significance.     

Successful treatment of immunoblastic lymphadenopathy-like T-cell lymphoma with cyclosporin A

Immunoblastic lymphadenopathy (IBL)-like T-cell lymphoma is considered to belong to peripheral T-cell lymphoma. Its prognosis is grave and effective treatments have not been established. Recently, we gave oral cyclosporin A (CsA) to a patient with IBL-like T-cell lymphoma, and succeeded in achieving dramatic remission. In this case, serum levels of interleukin-12 (IL-12) and tumor necrosis factor-alpha (TNF alpha) were elevated and decreased or returned to normal after achieving remission. Since CsA is a potent suppressor of the immune system and most notably T-cells, the immunosuppression of T-cell function might have played an important role in achieving remission in this case, although the precise mechanism still remains to be elucidated. The present case indicates that administration of CsA may be a very effective and safe selection of therapy for IBL-like T-cell lymphoma, as well as analogous disorders such as IBL and angioimmunoblastic lymphadenopathy with dysproteinemia (AILD), thereby will contribute to improving the prognosis of patients with these diseases.     

An immunological study on the effect of simultaneous intrahepatic injection of an immunomodulator (OK-432) and adriamycin--an experiment in rats

An immunological study of the effect of a simultaneous intrahepatic injection of adriamycin (ADM) and OK-432 (PIC) in seven-week-old S.D. rats was carried out. Three experimental groups included an ADM-PIC-0.5 group which was administered 0.5 mg/kg ADM and 0.5 KE/kg PIC, an ADM-PIC-1.0 group which was administered 1.0 mg/kg ADM and 1.0 KE/kg PIC and an ADM-PIC-2.0 group which was administered 2.0 mg/kg ADM and 2.0 KE/kg PIC. A control group was injected with normal saline. The numbers of T-cells, B-cells, helper T-cells and suppressor T-cells were counted before, 1 day after and 5 days after intrahepatic injection. The suppressor T-cell count decreased (p less than 0.05) in the ADM-PIC-0.5 group and the T-cell count (p less than 0.05), B-cell count (p less than 0.05), helper T-cell count (p less than 0.01), suppressor T-cell (p less than 0.05) and the ratio of suppressor T-cells among lymphocytes were decreased in the ADM-PIC-1.0 group. Decreases in the T-cell count (p less than 0.01), B-cell count (p less than 0.05), helper T-cell count (p less than 0.01), suppressor T-cell (p less than 0.01) and the ratio of suppressor T-cells among lymphocytes (p less than 0.01) were recognized in the ADM-PIC-2.0 group one day after injection. Five days after injection, the ratio of suppressor T-cells among lymphocytes (p less than 0.01) was decreased in the ADM-PIC-0.5 group, and suppressor T-cells (p less than 0.05) and the ratio of suppressor T-cells among lymphocytes were decreased in the ADM-PIC-1.0 group. In the ADM-PIC-2.0 group, suppressor T-cell count (p less than 0.01) and the ratio of suppressor T-cells among lymphocytes were decreased. The result suggested that a simultaneous intrahepatic injection with PIC could improve the immunosuppression produced by an intrahepatic injection of ADM.     

Transformation of CD8+ T-cells producing a strong cytopathic effect on CD4+ T-cells through syncytium formation by HTLV-II.

Human T-cell leukemia virus type II (HTLV-II) is thought to play an important role in the development of CD8+ T-cell malignancies resembling hairy cell leukemia. In this study, dramatic cytopathic effects characterized by syncytium formation in various CD4+ T-cell lines were observed upon their cocultivation with HTLV-II infected T-cells. The HTLV-II infected T-cells, however, did not die as a result of syncytium formation. HTLV-II also transformed CD4+ T-cells and CD8+ T-cells at various coculture ratios. Furthermore, sera from anti-HTLV-II antibody-positive specific carriers inhibited syncytium formation in the CD4+ T-cells. These results suggest that HTLV-II infection may contribute to the pathogenesis of associated CD8+ T-cell malignancies.     

Precursor T-cell lymphoma associated with human immunodeficiency virus type 1 (HIV-1) infection. First reported case

The majority of lymphomas that develop in human immunodeficiency virus type 1 (HIV-1) positive patients have a B-cell phenotype, with few reported cases of T-cell lymphoma. Within the latter group, those that have been comprehensively phenotyped had a mature helper T-cell phenotype (CD4+). We report, for the first time, an HIV-1 positive patient with a precursor T-cell lymphoma (CD7+,CD1-,CD3-,CD4-, and CD8-). T-cell receptor beta and gamma genes were in the germline configuration and integration of HIV-1 DNA could not be detected in the lymphoma cell genome.     

Transformation of CD8 + T-Cells Producing a Strong Cytopathic Effect on CD4+ T-Cells through Syncytium Formation by HTLV-II

Human T-cell leukemia virus type II (HTLV-II) is thought to play an important role in the development of CD8 + T-cell malignancies resembling hairy cell leukemia. In this study, dramatic cytopathic effects characterized by syncytium formation in various CD4+ T-cell lines were observed upon their cocultivation with HTLV-II infected T-cells. The HTLV-II infected T-cells, however, did not die as a result of syncytium formation. HTLV-II also transformed CD4 + T-cells and CD8 + T-cells at various coculture ratios. Furthermore, sera from antiHTLV-II antibody-positive specific carriers inhibited syncytium formation in the CD4+ T-cells. These results suggest that HTLV-II infection may contribute to the pathogenesis of associated CD8 + T-cell malignancies.     

Reduced incidence of Marek's disease gross lymphomas in T-cell-depleted chickens.

Chickens of line 7, highly susceptible to Marek's disease (MD), were depleted of T-cells by neonatal thymectomy, total-body gamma-irradiation, and multiple injections with antithymocyte serum. In two replicate experiments, significantly fewer gross lymphomas were present in T-cell-depleted chickens than in intact or in T-cell-depleted, reconstituted hatchmates; these findings provided evidence that T-cells may be the principal target for MD virus (MDV) transformation, T-cell depletion was not complete, and the presence of microscopic lesions in T-cell-depleted chickens was attributed to residual T-cells. Ten lymphomas from intact chickens and 2 lymphomas from a T-cell-depleted chicken were examined for cellular composition. All lymphomas consisted predominantly of T-cells. The results of this and other published studies indicated that T-cells may have a dual role in MD; They may serve as a target for lymphoma formation by MDV and also may participate in immune surveillance against the disease in resistant chickens.     

Establishment of an IL-2 independent, human T-cell line possessing only the p70 IL-2 receptor

A continuous cell line was established from the blood of a patient (HH) with an aggressive cutaneous T-cell leukemia/lymphoma who lacked antibodies to human T lymphotrophic virus, type I. The immunophenotype of the cultured cells was CD2+, CD3+, CD4+, CD5+, CD8-, DR+ and CD25- (Tac, IL-2 receptor alpha chain). Southern-blot hybridization analysis of T-cell-receptor beta chain DNA demonstrated the same rearrangement in freshly isolated blood cells and cultured cells, indicating that the cell line was derived from the patient's malignant clone. Since cultured T-cells grew in complete medium without added IL-2, we investigated whether HH cells could be producing and responding to IL-2 in an autocrine fashion. However, no IL-2 was detectable in supernatant from the cell line, while antibodies to IL-2, or to the IL-2 receptor alpha or beta chains did not inhibit cell growth. In addition, no mRNA message for IL-2 was detectable in these cells. The results appear to exclude an autocrine IL-2-dependent mechanism of cell growth for this T-cell line. Although cultured HH cells lacked detectable IL-2 receptor alpha chain, they did show increased proliferation to exogenous IL-2. Binding studies with 125I-IL-2 demonstrated an intermediate affinity receptor for IL-2, KD = 1.7 nM, with 6400 binding sites per cell, suggesting the presence of an IL-2 receptor beta chain. Consistent with these findings 125I-IL-2 cross-linking studies demonstrated a single receptor calculated to be 75 kDa. Also, the beta chain of the IL-2 receptor was detected by immunofluorescence using specific monoclonal antibodies (MAbs). Nanomolar concentrations of an IL-2-diphtheria toxin fusion protein inhibited cellular protein synthesis, an effect abrogated by native IL-2. These findings indicate that the IL-2 receptor beta-chain was functional. This novel mature T-cell line may be useful in studies of IL-2 receptor regulation and in analysis of the mechanism of T-cell leukemogenesis.     

Loss of p27(Kip1) cooperates with cyclin E in T-cell lymphomagenesis

Cyclin E and p27(Kip1) are key regulators for cyclin-dependent kinases (Cdks) acting at the G1-/S-phase transition of the cell cycle. Whereas cyclin E is required for the activation of Cdk2, p27(Kip1) is a specific Cdk inhibitor and can block cell division. High levels of cyclin E and low levels of p27(Kip1) expression have been associated with malignant lymphomas in humans; the level of p27(Kip1) is even considered of prognostic significance. However, mice that lack p27(Kip1) do not develop any malignant lymphomas despite a pronounced lymphoid hyperplasia in thymus and spleen. We have previously described transgenic mice that carry a construct in which the cyclin E cDNA is under the control of the CD2 promoter/enhancer region and thus express high levels of cyclin E in the T-cell compartment (CD2-cyclin E). These animals are not predisposed for T-cell lymphomas in the absence of other cooperating events. Here we show that T-cells from CD2-cyclin E mice that at the same time are deficient for p27(Kip1) show a significantly higher Cdk2 activity than cells from wild-type or single mutant animals. Accordingly, a higher percentage of T cells in S/G2/M phase is found in CD2-cyclin E/p27(Kip1-/-) mice. After a long latency period of over 200 days, these animals develop spontaneous monoclonal T cell lymphoma whereas none of the single CD2-cyclin E transgenic or the p27(Kip1)-deficient mice showed any sign of lymphoid malignancies. Our findings demonstrate that a deregulation of control mechanisms at the G1/S transition by the combination of high cyclin E levels in the absence of p27(Kip1) is sufficient to predispose mice to develop lymphoid malignancies and further support a role of p27(Kip1) as a tumor suppressor and of cyclin E as a dominant oncogene.     

Antilymphoma activity of human gamma delta T-cells in mice with severe combined immune deficiency.

Human Burkitt lymphoma (Daudi) cells grow as disseminated tumors in mice with severe combined immune deficiency (SCID) after either i.v. or i.p. injection. These cells are lysed in vitro by human V gamma 9/V delta 2 T-cells that recognize the groEL homologue on the Daudi cell surface. We report that both Daudi cell-stimulated peripheral blood mononuclear cells (Daudi-PBMC) containing 41-95% of V gamma 9/V delta 2 T-cells and V gamma 9/V delta 2 T-cell clones prolong the survival of SCID mice given inoculations of a lethal dose of Daudi cells. Groups of 6-8-week-old SCID mice were given inoculations i.v. or i.p. of 10(5) Daudi cells followed (through different injection sites) by: (a) 10(7) Daudi-PBMC; or (b) 10(7) unstimulated PBMC; or (c) 0.9% saline solution. All animals in groups (b) and (c) died of disseminated lymphoma, and their survival was significantly shorter than that of mice in group (a) (P < 0.001 for both i.v. and i.p. routes). Significant antitumor effects were also detected when Daudi-PBMC were injected 4 days before or 4 days after Daudi cells (P < 0.05). In vivo depletion of murine natural killer cells by anti-asialo GM-1 rabbit antiserum did not affect survival, suggesting that these cells did not contribute to lymphoma killing. Daudi-PBMC did not exert in vivo antitumor activity against the control Raji lymphoma. Mice receiving i.p. injections of Daudi cells followed by cytotoxic V gamma 9/V delta 2 T-cell clones also survived significantly longer (P < 0.05 for 3 different clones) than animals given Daudi cells alone or Daudi cells followed by noncytotoxic gamma delta T-cell clones. Our results indicate that this model system can be used for studies of human antilymphoma T-cell responses in vivo.     

Epitheliotropic lymphoma of the small bowel. Report of a fatal case with cytotoxic/suppressor T-cell immunotype

The authors report the clinical, pathologic, and immunologic features of a case of jejunal cytotoxic/suppressor T-cell lymphoma associated with intractable malabsorption. Histologically, the tumor exhibited striking involvement of small bowel surface and glandular epithelium, and of epithelium in sites of disease dissemination. This epitheliotropism consisted of both cell clusters resembling Pautrier 's microabscesses and single cells within epithelium. Grossly, the jejunal mucosal fold pattern was completely obliterated by lymphoma which formed miliary nodules and multiple distinct tumor masses. Despite aggressive chemotherapy the patient developed widespread disease, and died 11 months after presentation. At autopsy, in addition to disseminated lymphoma, there was a notable activation of hematopoiesis evidenced by extensive extramedullary hematopoiesis and bone marrow hypercellularity. Many lymph nodes spared by the lymphoma showed a polyclonal proliferation of plasma cells and immunoblasts. In view of recent immunologic evidence that normal cytotoxic/suppressor T-cells selectively home to the gut surface epithelium, striking tumor cell epitheliotropism may be a morphologic marker for visceral lymphomas of cytotoxic/suppressor T-cell origin. This unique case broadens the clinical and morphologic spectrum of T-cell disorders.