Induction of T cell differentiation and lymphomagenesis in the thymus of mice with severe combined immune deficiency (SCID)

William J Murphy, Scott K. Durum, Miriam R. Anver, Douglas K. Ferris, Daniel W. McVicar, John J. O'Shea, Sandra K. Ruscetti, Mark R. Smith, Howard A. Young, Dan L. Longo

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52 Scopus citations

Abstract

Severe combined immune deficiency (SCID) mice have a defect in their recombinase system and cannot productively rearrange their immune receptor genes. Thus, SCID thymocytes are arrested at the immature 'triple negative' phase, not expressing CD3, CD4, or CD8 surface markers. Whole body irradiation of SCID mice induced maturation of their thymocytes to the CD4+/CD8+ double positive, CD3(+low) stage of differentiation, and resulted in the generation of a thymic cortical region on histologic examination. No mature single positive T cells were detected in the thymus or the periphery. VDJ rearrangements of TCR-β with restricted clonality were observed in the double positive cells from a given individual. The CD3 complex was expressed on some of these cells, but the cells failed to mobilize intracellular calcium after cross-linking with CD3 Abs. The double positive cells appeared several weeks after irradiation, persisted for many months in the thymus, and by 6 mo generally developed into metastatic lymphoma. Retroviral activation was undetectable in both the preneoplastic and transformed thymocytes. Thus, it appears that the earliest steps in T cell development can be induced in SCID mice by inducing DNA breaks with radiation. This system represents a model of early thymic development, preneoplasia, and neoplasia.

Original languageEnglish (US)
Pages (from-to)1004-1014
Number of pages11
JournalJournal of Immunology
Volume153
Issue number3
StatePublished - Aug 1 1994
Externally publishedYes

ASJC Scopus subject areas

  • Immunology

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    Murphy, W. J., Durum, S. K., Anver, M. R., Ferris, D. K., McVicar, D. W., O'Shea, J. J., Ruscetti, S. K., Smith, M. R., Young, H. A., & Longo, D. L. (1994). Induction of T cell differentiation and lymphomagenesis in the thymus of mice with severe combined immune deficiency (SCID). Journal of Immunology, 153(3), 1004-1014.