The early thymic precursor population of adult mice (low CD4 precursor) has the potential to produce T cells, B cells and dendritic cells if transferred into the appropriate inductive environment of an irradiated recipient. To assess its developmental potential in vitro, this population was isolated and cultured, alone and with various stromal cell lines. Cultured alone, these precursor cells all died rapidly. Co-culture with 3T3 fibroblasts gave good survival but no growth. Co-culture with thymic cortical epithelial cell lines induced significant proliferation after an initial 50% cell loss. However, the supernatant of these cortical epithelial cell lines caused only limited proliferation after very extensive cell death. Examination of the surface phenotype of the cultures on the cortical epithelial layer showed some changes which were compatible with very early steps of thymocyte development, but none of the features of more developed T cells were seen. A proportion of the proliferating cells developed some of the surface markers and morphology of dendritic cells. Immature myeloid cells also grew in these cultures; these appeared to derive from a small number of myeloid progenitors, possibly contaminants within the preparation, and their outgrowth required only soluble factors released by the cortical epithelial cells.

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A linkage between dendritic cell and T-cell development in the mouse thymus: the capacity of sequential T-cell precursors to form dendritic cells in culture.

The earliest T precursor population in the adult mouse thymus (CD4lo8-3-44+25-c-kit+) was previously shown to be lymphoid-restricted (T, B, NK) but to have a capacity to form dendritic cells (DC). This led to the concept of a lineage of lymphoid-derived DC. DC could be generated with high efficiency in culture from this low CD4 precursor, using a complex mix of cytokines, a mix that notably did not include GM-CSF, the cytokine normally used for development in culture of myeloid-derived DC. Using this new culture system we now show that the capacity to form DC extends to the pro-T precursor population (CD4-8-3-44+25+c-kit+) but is lost by the pre-T precursor stage (CD4-8-3-44-25+c-kit+), the point of T-cell antigen-receptor beta-gene rearrangement. The DC generated in the cultures resemble mature thymic DC by most markers, but differ in their lack of expression of BP-1 and CD8 alpha.

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T-cell development in the thymus.

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Mouse strain differences in subset distribution and T cell antigen receptor expression among CD4-CD8- thymocytes.

'Double negative' (CD4-CD8-) thymocytes from adult mice of different inbred strains were examined for surface expression of CD3 and of various forms of the T cell antigen receptor (TcR), as well as for the levels of subpopulations defined by the surface markers HSA ('heat stable antigen', recognized by M1/69, J11d and B2A2), CD5 (Ly 1) and Thy 1. Marked variations were found in the level of the double negative subsets which were surface TcR+, or which were HSA-CD5+; these generally varied together since most CD4-CD8-HSA-CD5+ thymocytes were TCR+. The level of the CD3-TCR complex on the surface of those double negative thymocytes which were TcR+ was as high as on mature T cells in some strains (CBA/Ca), but was much lower in other strains (C57BL/6J). In most mouse strains the CD4-CD8-HSA-CD5+ thymocytes expressed predominantly the alpha beta form of the TcR, with an exceptionally high (70%) usage of V beta 8 gene products. In strains which lacked V beta 8 expressing T cells due to a deletion of the V beta 8 gene region, reduced levels of alpha beta TcR+ cells were found within the CD4-CD8- thymocytes; the HSA-CD5+ subset was then only present at low levels (as in SJL/J and C57BR mice) or was present at a high level but expressed predominantly gamma delta TcR (as in SWR mice). The results suggest that the accumulation of CD4-CD8-TcR+ HSA-CD5+ thymocytes is a selective event, and that their developmental pathway is off the mainstream of T cell maturation in the thymus.

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