Nucleotide sequences of VJ (variable-joining) junctional regions of V14' a-chain T-cell receptor genes show that most VaW4+ T cells use one a chain (Val4Ja281 with a one-nucleotide N region, which is frequently used in keyhole limpet hemocyanin-specific suppressor T-celi hybridomas) in unprimed mice. Moreover, the frequency of this a-chain expression was >1.5% of the total a chains found in laboratory strains, including B10 congenic mice. This is about 104 times higher than was expected. The V14J281 a-chain expression was relatively low but was significant in CD41/CD81 immature thymocytes and became quite high in mature single-positive T cells, implying that this a chain is selected during T-cell maturation. V14J281 expression increased with time after birth and reached a maximum at around 5 weeks of age. The ligand seems to be a self molecule and to be present in laboratory strains but to be absent in a wild mouse, Mus musculus molossinus, because bone marrow chimeras clearly showed that bone marrow cells derived from Mus musculus molossinus negative for this a chain raised V14J281-positive T cells in a C57BL/6 environment. The above results suggest that there are some selection mechanisms for this cell type other than those for conventional afi T cells and also that the homogenous VJ junction of the V14J281 a chain plays a pivotal role in the selection of the T cell and its ligand reactivity.Thymus-derived lymphocytes (T cells) recognize antigens in the context of the polymorphic parts of major histocompatibility complex (MHC) class I or class II molecules by virtue ofthe heterodimeric a/3 T-cell receptor (TCR), which is found on the vast majority of mature T cells in the thymus and peripheral lymphoid tissues (1, 2). A second TCR, y8 TCR, has also been identified (3, 4) and found to be relatively abundant in some adult mouse organs and among fetal thymocytes.The T-cell repertoire seems to be generated by two selection mechanisms during T-cell We provide evidence herein that some T cells use a homogenous a chain (V14J281). This seems to be a consequence of selection and expansion ofthis T-cell type, because its frequency is >1.5% of the total a chains in the peripheral lymphoid organs. Moreover, studies using bone marrow chimeras suggest that the ligand is an unidentified self molecule. The results indicate that the homogenous VJjunctional region of the V14J281 a chain, in particular, plays a crucial role in the selection of this type of T cell and its ligand reactivity. MATERIALS AND METHODSAnimals and Cell Lines. Pathogen-free C57BL/6 mice were purchased from Shizuoka Experimental Animal Co., Hamamatsu, Japan. A wild Japanese mouse strain, Mus musculus molossinus, was established and maintained by K.M. Other strains, including B10 congenic lines used, were also maintained by K.M. A thymoma cell line of AKR origin, BW5147, and a keyhole limpet hemocyanin (KLH)-specific suppressor T-cell (Ts) hybridoma (BW5147 x C57BL/6 Ts; 34S-281) used in the present studies have been described (12,13

Dietary restriction, especially caloric restriction, is a major modifier in experimental carcinogenesis and is known to decrease significantly the incidence of neoplasms. (1986) Proc. Natl. Acad. Sci. USA 83, 7928-7931] reported that a 36% restriction in caloric intake dramatically decreased the radiation-induced solid tumors and͞or leukemias. Their protocol predominantly produced lymphatic neoplasms. It is of interest to observe the effect of caloric restriction on radiation-induced myeloid leukemia, because the disease was observed to have been increased in the survivors of the atomic bombs in Hiroshima and Nagasaki. The spontaneous incidence of myeloid leukemia in C3H͞He male mice is 1%, and the incidence increased to 23.3% when 3 Gy of whole-body x-ray irradiation was given. However, the incidence of myeloid leukemia was found to be significantly decreased by caloric restriction; it was reduced to 7.9% and 10.7% when restriction was started before (6 weeks old) and after (10 weeks old) irradiation, respectively. In addition, the onset of the myeloid leukemia in both restricted groups was prolonged to a greater extent as compared with the control diet group. Caloric restriction demonstrated a significant prolongation of the life span in the groups on a restricted diet after having been exposed to irradiation, either before or after dietary restriction, in comparison with mice that were only irradiated.Dietary restriction, especially caloric restriction, is a major carcinogenic modifier during experimental carcinogenesis and is known to decrease significantly the spontaneous (1-4) and induced incidence by chemicals (5-7). Much less is known about the effect of dietary restriction on the radiation carcinogenesis͞leukemogenesis, and four reports have been published concerning the effects on radiation-induced tumorigenesis. Reports by showed that dietary and͞or calorie restriction could also reduce the incidence of radiation-induced neoplasms (8-11). In their reports, a dietary restriction of 36% dramatically decreased radiationinduced tumors and͞or leukemias. Since their protocol of five consecutive total-body ␥-irradiations of 1.50 Gy each, given at weekly intervals, produced predominantly lymphatic neoplasms, with a higher incidence of thymic lymphomas, their observations were limited to lymphatic neoplasms (8-11). It is of interest to explore the effect of caloric restriction on radiation-induced myeloid leukemia as an experimental model, because this disease is known to be one of the ultimate human leukemias that has significantly increased in the survivors of the atomic bombs in Hiroshima and Nagasaki (12, 13).Experimental myeloid leukemia in C3H͞He male mice was increased from 1% to 23.3% after exposure to 3 Gy x-ray irradiation (14). The incidence also has been modified and was increased up to Ϸ40% by either a single dose of prednisolone or the induced aseptic inflammation (14, 15). Thus, the system seems to be an excellent animal model for studying modifications by caloric restriction on the rad...

Ikaros (now known as Znfn1a1), a Krüppel-type zinc-finger transcription factor that plays a critical role in both lineage commitment and differentiation of lymphoid cells, has recently been shown to function as a tumor suppressor gene. We have previously reported a high frequency of LOH (approximately 50%) at the Znfn1a1 locus in radiation-induced T-cell lymphoma in susceptible B6C3F1 mice. The aim of the present study was to delineate the types of Znfn1a1 inactivation, with special reference to the LOH status, and to determine the relative contribution of each type of Znfn1a1 inactivation in radiation-induced T-cell lymphomas in B6C3F1 mice. We demonstrated that Znfn1a1 was frequently altered (in approximately 50% of T-cell lymphomas), and that its inactivation was caused by a variety of mechanisms, which came under one of the following four categories: (1) null expression (14%); (2) expression of unusual dominant-negative isoforms (11%); (3) amino acid substitutions in the N-terminal zinc-finger domain for DNA binding caused by point mutations (22%); (4) lack of the Znfn1a1 isoform 1 due to the creation of a stop codon by insertion of a dinucleotide in exon 3 (3%). The null expression, amino acid substitutions, and dinucleotide insertion inactivation types were well correlated with LOH at the Znfn1a1 allele (86%) and were consistent with Knudson's two-hit theory. On the other hand, T-cell lymphomas expressing dominant-negative Znfn1a1 isoforms retained both alleles. These results indicate that Znfn1a1 inactivation takes place by a variety of mechanisms in radiation-induced murine T-cell lymphomas and is frequently associated with LOH, this association depending on the type of inactivation.

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