The origin of DN T cells is still unclear
The origin of DN T cells is still undeciphered, with different studies obtaining contrasting results. To date, no study has provided direct evidence that DN T cells derive from CD4+ T or CD8+ T cells. Some researchers believe that DN T cells derive from CD4+ T or CD8+ T cells that pass through positive selection and have down-regulated expressions of CD4 or CD8 26, 35, 36, 38, 39. Other researchers believe that DN T cells derive from CD4+ T cells 38, 39; evidence suggests that DN T cell frequency significantly increased in purified CD4+ T cells in vitro and that rIL-2 and rIL-15 enhance the conversion of CD4 T cells to DN T cells via allogeneic mature BM DC stimulation 39. In addition, recent research has shown that CD4+CD138+ T cells in an SLE murine model exhibited downregulated CD4 expressions and simultaneously expressed B220 (unpublished data in preview by Tianhong Xie et al.), which is commonly expressed on the surfaces of DN T cells and nonselected CD8+ T cells 26. It was previously believed that these nonselected B220+CD8+ T cells were the precursor from which DN T cells were derived 26. We speculate that B220+CD4+CD138+ T cells may be the precursors that are converted into DN T cells, which in turn are derived from CD4+ T cells. This remains unclear, however, and more evidence is needed regarding whether B220+CD4+CD138+ T cells are able to further convert to CD138+ DN T cells.
Some researchers have suggested that DN T cells instead derive from CD8+ T cells. The idea that DN T cells originate from CD8+ T cells is mainly based on the evidence that the hypomethylation of the gene loci encoding the CD8 coreceptor in DN T cells indicates the previous expression of CD8 in DN T cells 9. Treatment with an anti-CD8 mAb has been shown to significantly prevent the accumulation of DN T cells in lupus mice 35. Previous studies have also found that the expansion of DN T cells is regulated by MHC-I36. The downregulation of the surface expression of CD8 has also been observed in the activated CD8+ T cells of lupus mice, after T-cell receptor stimulation 40, 41. Additionally, one study has provided a new insight into the origin of DN T cells, proposing that DN T cells may originate from non-selected autoreactive CD8+ T cells 26, 42, which co-express CD44 and B220 26. Defects in Fas signaling lead to the IL-15/IL-2-dependent survival of non-selected CD44+B220+CD8+ T cells and DN T cells 26. Some researchers have even proposed the idea that DN T cells do not derive from either CD4+ T or CD8+ T cells10. Instead, they have suggested that DN T cells derive from immature double positive thymocytes that downregulate the expressions of CD4 and CD8 to convert into bona fide DN T cells10. It has been speculated that DN T cells may accumulate owing to the dysfunction of apoptosis induced by Fas deficiency 10.