Radiation leukemia virus-induced thymic lymphomas express a restricted repertoire of T-cell receptor V beta gene products

Abstract

We have investigated the phenotypic changes that take place during the process of neoplastic transformation in the thymocytes of C57BL/Ka mice infected by the radiation leukemia virus (RadLV). By the combined use of antibodies against the envelope glycoprotein gp7O of RadLV, the transformation-associated cell surface marker lC1l, and the CD3-T-cell receptor (TCR) complex, we found that in the RadLV-infected thymus, the earliest expression of viral gp7O is in lCllhi cells; a small but significant percentage of these cells also express CD3. A first wave of viral replication, manifested by the expression of high levels of gp7O in thymocytes (over 70% positive), reaches a peak at 2 weeks; during this period, no significant changes are observed in the expression of IC11 or CD3. The population of gp70+ cells is drastically reduced at 3 to 4 weeks after infection. However, a second cohort of gp70+ cells appears after 4 weeks, and these cells express high levels of lCll and TCR determinants as well. RadLV-induced lymphomas differ from normal thymocytes in their CD4 CD8 phenotype, with domination by one or more subsets. Characterization of TCR gene rearrangements in RadLV-induced lymphomas shows that most of these tumors are clonal or oligoclonal with respect to the JP2 TCR gene, while the Jjll TCR gene is rearranged in a minority (4 of 11) of lymphomas. TCR VP repertoire analysis of 12 tumors reveals that 6 (50%o) express exclusively the V,I6 gene product, 2 (17%) are V05', and 1 (8%) each are VP8+ and VP9+. In normal C57BL/Ka mice, VPI6 is expressed on 12%, VII5 is expressed on 9%, V,B8 is expressed on 22%, and Vj89 is expressed on 4% of TCRhi thymocytes. Thus, it appears that RadLV-induced thymic lymphomas are not randomly selected with respect to expressed TCR VP type. Exposure to ionizing radiation is known to induce lymphoid malignancy in humans; the incidence of acute lymphoblastic leukemia in particular has been shown to correlate with radiation dose (34). To facilitate investigation of the basic mechanisms by which radiation induces leukemia, Kaplan and colleagues developed a murine model (21, 22) which they used to define the parameters for T-cell transformation. Wholebody irradiation, administered in fractionated doses, was found to induce a high incidence (>90%) of thymus-dependent lymphomas in C57BL/Ka mice (22). A thymotropic and lymphomagenic retrovirus, the radiation leukemia virus (RadLV), was recovered from cell extracts of some of these lymphomas (29, 30). After serial in vivo passage, RadLV-induced thymic lymphomas were found to be similar in frequency, clinical aspects, and latency to those produced by radiation. Several lymphoma cell lines from RadLV-induced tumors were established in culture (27); one such cell line, BLNVL3, was used to

Predominant T-cell receptor Vbeta usage of intraepithelial lymphocytes during the immune response to enteric reovirus infection

“…However, for other viral systems the relationship between oligoclonal expansion of certain TCR subpopulations and CTL responses has been confusing. Some studies have agreed with our findings that oligoclonal expansion of certain TCR subpopulations occurred following virus infection (12,38,39,42). These include data from humans infected with human immunodeficiency virus, in which a patient had a profound increase in the percentage of CD8 ϩ T cells bearing TCR V␤19, with some of these cells having CTL responses toward human immunodeficiency virusinfected cells.…”

“…There is evidence to support the notion that virus infection selectively induces monoclonal or oligoclonal expansion of certain TCR subpopulations, such as V␤8.3 T cells in influenza (12), V␤6, -5, -8, and -9 T cells in virus-induced thymic lymphomas (39), and V␤10, -8, and -13 T cells in acute myocarditis caused by coxsackievirus (38). However, the TCR utilization of IEL during the mucosal immune response to virus invading the gastrointestinal mucosa has not been studied previously.…”

“…Even though T cells bearing the ␥/␦ TCR comprise a high proportion of the IEL, intraepithelial T cells bearing the ␣/␤ TCR are responsible for the specificity of CTL for intracellular pathogens such as viruses (6,28,32). A role for specific subsets of T cells bearing V␣ and V␤ TCRs has been postulated due to preferential interactions with the major histocompatibility complex (MHC) (9,11), and these interactions may account for the preferential use of TCR variable genes in some virus-induced diseases (12,34,39).…”