T cell receptor-negative thymocytes from SCID mice can be induced to enter the CD4/CD8 differentiation pathway
✍ Scribed by Elizabeth W. Shores; Susan O. Sharrow; Ingeborg Uppenkamp; Alfred Singer
- Publisher
- John Wiley and Sons
- Year
- 1990
- Tongue
- English
- Weight
- 994 KB
- Volume
- 20
- Category
- Article
- ISSN
- 0014-2980
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✦ Synopsis
Introduction T cell receptor-negative thymocytes from SCID mice can be induced to enter the CD4/CD8 differentiation pathway
In order to investigate the role of Tcell receptor (TcR) expression in thymocyte maturation, we have analyzed thymocytes from C.B-l7/SCID mice, which are unable to productively rearrange their antigen receptor genes and fail to express TcR. Despite this defect, SCID thymocytes are functional as they produce lymphokines and proliferate in response to a variety of stimuli. Phenotypic analysis revealed that thymocyte populations from young adult SCID mice resemble thymocyte populations from normal embryonic mice in that they are large, Thy-1.2+, CD4-, CD8-, TcR-and enriched in CD5I0, IL2R+ and Pgpl+ cells. However, other TcR-populations normally present in adult mice ( i e . , CD4-CD8+ cells and CD4+CD8+ cells) are absent from the thymus of TcR-adult SCJD mice. To understand the basis of the developmental arrest of TcR-SCID thymocytes at the CD4-CD8-stage of differentiation, we analyzed thymi from the occasional "leaky" SCID mouse which possesses small numbers of TcR+ thymocytes. We found that the presence of TcR+ cells within a SCID thymus was invariably associated with the presenceof CD4+ and/or CD8+ SCID thymocytes. Interestingly, however, the CD4+/CD8+ SCID thymocytes were not themselves necessarily TcR+. That is, emergence of SCID thymocytes expressing CD4/CD8 was tightly linked to the presence of TcR+ cells within that SCID thymus, but the SCID thymocytes that expressed CD4/CD8 were not necessarily the same cells that expressed TcR. Finally, we found that the introduction into TcR-SCID mice of normal bone marrow cells that give rise toTcR+ cells within the SCID thymus promoted the differentiation of SCID thymocytes into CD4-CD8+ and CD4+CD8+ TcR-cells. These data indicate that TcR+ cells within the thymic milieu provide critical signals which promote entry of CD4-CD8-TcR-precursor T cells into the CD4/CD8 differentiation pathway. When applied to differentiation of normal thymocytes, these findings may imply a critical role for early appearing CD4-CD8-TcR (y/6)+ cells in initiating normal thymic ontogeny.
Within the inductive environment of the thymus, TcRprogenitor cells differentiate into mature TcR+ Tcells that are restricted to self MHC molecules and tolerant to self antigens [l-31. These early TcR-progenitor cells do not themselves express CD4 or CD8 determinants, but do possess the capacity to differentiate into all CD4/CD8 thymocyte subsets (i.e., CD4+CD8+, CD4+CD8-and CD4-CD8+ thymocytes) [4-61. The forces driving the differentiation of immature TcR-thymocytes into the CD4/CD8 differentiation pathway have not been well characterized. In the present study, we have assessed the relationship between cell surface TcR expression and the [I 78021