Shuji Takagi

Three novel mutations in the interleukin-2 receptor γ chain gene in four Japanese patients with X-linked severe combined immunodeficiency

Three novel mutations in the IL-2Rγ chain gene were identified in four Japanese patients with X-linked severe combined immunodeficiency by direct sequence analysis of polymerase chain reaction (PCR) amplified DNA fragments.

Phenotypical and functional heterogeneity of the large granular lymphocytes increased after various treatments in a patient with combined immunodeficiency

A boy with combined immunodeficiency having low natural killer (NK)-cell activity received thymopoietin pentapeptide (TP-5) treatment, transplanted with T cell-depleted HLA-haploidentical bone marrow (BMT) cells from his father and with thymus tissue from an infant at different times during the first year of life. He showed a marked increase in large granular lymphocytes (LGL) both during the treatment with TP-5 and after BMT. The LGL generated following TP-5 injection had a T3+ Leu 11− surface phenotype and low NK activity. In contrast, the LGL appearing after BMT showed T3−, Leu7+, and/or Leu11+ surface phenotypes, had high NK- and K-cell activities, and were lymphokine-activated killer (LAK)-cell precursors. These killer activities were assigned to the Leu7− Leu11+ subset and proved to be of recipient origin. LGL proliferation following BMT was accompanied by neutropenia, which was improved in association with a reduction in the number of LGL and the appearance of T cells of BMT donor origin following thymus transplantation. This suggested the inhibition of granulopoiesis by the LGL and anin vitro study revealed that the Leu7+ Leu11− subset of LGL suppressed the growth of granulocyte/macrophage colony-forming units. These results indicated that phenotypically different LGL could be generated by different treatments and that the LGL showing NK activity were distinct from those regulating granulopoiesis. It was also suggested that the generation of LGL was controlled by T cells.

Immunoregulatory function and expression of OKT17 antigen of adult T‐cell leukemia cells

Research was carried out on neoplastic T‐cells taken from 10 cases of Japanese adult T‐cell leukemia (ATL) in regard to their immunoregulatory activity on pokeweed mitogen (PWM)‐driven immunoglobulin (Ig) production and their differentiation antigens. ATL cells were reactive with OKT3, OKT4 and OKT11 in most cases; however, the ATL cells from one case did not react with OKT11 nor formed E‐rosettes. ATL cells of three cases were reactive with OKT8 as well as OKT4. In six cases, the ATL cells were reactive with OKT17 and coincidentally displayed suppressor activity on Ig production. The cells of the remaining four cases did not have such reactivity with OKT17 or suppressor activity. Moreover, the OKT17(+) ATL cells from one case sorted by FACS 440 demonstrated suppressor activity, while the OKT17(−) ATL cells did not. These results indicated that ATL cells with suppressor activity had OKT3(+), OKT4(+), OKT17(+) phenotype.

Generation and Function of αδ T Cells after Allogeneic Bone Marrow Transplantation in Humans: Comparison in Absence or Presence of HLA‐Matched or Mismatched Thymus

We have observed two patients who exhibited an exclusive increase of δ TCS1+ subset of αδ T cells in the peripheral blood after bone marrow transplantation (BMT). In one case with severe combined immunodeficiency (SCID) who received haploidentical BMT from his father, αδ T cells appeared only after thymus transplantation. However, his T cell‐mediated immunity remained severely defective despite the generation of T cells of donor origin. In the other case with aplastic anemia, δ T CS1‐αδ T cells began to increase in the peripheral blood later. This indicates that the thymus is necessary for the generation of αδ T cells and that the δ TCS1+ subset is dominant in the early stages of their ontogeny. δ TCS1+ T cell lines were established from both patients, and allo‐reactivity was investigated. The cell line from the latter case reacted to recipient cells in a mixed lymphocyte reaction, but did not show cytotoxity to the allogeneic cells including recipient cells. The other cell line, from the former case, did not react to either donor or recipient cells. This indicates that an intact thymus is needed for αδ T cells to acquire allo‐reactivity. Both cell lines showed MHC non‐restricted cytotoxity against NK‐sensitive target cells.

Differences of LAK-activity and IL-2 responsiveness between α/β and γ/δ T cells which developed after thymus transplantation

A patient with severe combined immunodeficiency was transplanted with T cell depleted haploidentical bone marrow from his father and was later given a thymic graft from an unrelated donor, α/β and γ/δ T cells of bone marrow donor origin appeared only after the thymus transplantation procedure. Among the peripheral blood lymphocytes (PBL), γ/δ T cells comprised 10–20% and most of them were δTCS1+. The α/β T cells were single positive cells, either CD4+ or CD8+. Expression of CD5, CD7 and CD8α,β molecules on α/β T cells was reduced. Functional studies showed that γ/δ T cells proliferated slightly in response to anti‐CD3 stimulation, and proliferated well with exogenous IL‐2 stimulation, while α/β T cells did not proliferate following mitogenic stimulation even in the presence of IL‐2. γ/δ T cells but not α/β T cells exhibited some LAK activity after culturing with IL‐2. Since α/β T cells expressed IL‐2R α and β chains after mitogenic stimulation and bound IL‐2, the deficit(s) in these cells was considered to occur after IL‐2 binding to the IL‐2R. These results indicate thymic dependency of both types of T cells and that two types of T cells differed in the acquisition of IL‐2 responsiveness during development.