IL-15 Expands Unconventional CD8ααNK1.1+ T Cells but Not Vα14Jα18+ NKT Cells

Abstract

Despite recent gains in knowledge regarding CD1d-restricted NKT cells, very little is understood of non-CD1d-restricted NKT cells such as CD8+NK1.1+ T cells, in part because of the very small proportion of these cells in the periphery. In this study we took advantage of the high number of CD8+NK1.1+ T cells in IL-15-transgenic mice to characterize this T cell population. In the IL-15-transgenic mice, the absolute number of CD1d-tetramer+ NKT cells did not increase, although IL-15 has been shown to play a critical role in the development and expansion of these cells. The CD8+NK1.1+ T cells in the IL-15-transgenic mice did not react with CD1d-tetramer. Approximately 50% of CD8+NK1.1+ T cells were CD8αα. In contrast to CD4+NK1.1+ T cells, which were mostly CD1d-restricted NKT cells and of which ∼70% were CD69+CD44+, ∼70% of CD8+NK1.1+ T cells were CD69−CD44+. We could also expand similar CD8ααNK1.1+ T cells but not CD4+ NKT cells from CD8α+β− bone marrow cells cultured ex vivo with IL-15. These results indicate that the increased CD8ααNK1.1+ T cells are not activated conventional CD8+ T cells and do not arise from conventional CD8αβ precursors. CD8ααNK1.1+ T cells produced very large amounts of IFN-γ and degranulated upon TCR activation. These results suggest that high levels of IL-15 induce expansion or differentiation of a novel NK1.1+ T cell subset, CD8ααNK1.1+ T cells, and that IL-15-transgenic mice may be a useful resource for studying the functional relevance of CD8+NK1.1+ T cells.

Thymic and peripheral microenvironments differentially mediate development and maturation of iNKT cells by IL-15 transpresentation

“…Our finding of IL-15-mediated proliferation is in contrast to the lack of proliferation of iNKT cells observed in IL-15 Tg mice. 43 In this IL-15 Tg model, the excess IL-15 produced probably binds to the many cell types expressing IL-15R␣, which do not normally 27 we found that the presence of IL-15R␣ also increased the proliferation of immature hepatic CD44 High NK1.1 Ϫ cells. Because proliferation of immature CD44 High NK1.1 Ϫ cells was modulated by IL-15 in the liver but not in the thymus, it suggests that the type of IL-15 response is better dictated by the microenvironment than the stage of differentiation.…”

Functionally Mature CD4 and CD8 TCRαβ Cells Are Generated in OP9-DL1 Cultures from Human CD34+ Hematopoietic Cells

“…A prominent population of CD8␣␣ TCR␣␤ cells was described in IL-15-transgenic animals (47). These cells were MHC class I dependent, since these were not observed in ␤ 2 -microglobulin knockout mice but were detected in CD1d knockout mice.…”

Human MAIT and CD8αα cells develop from a pool of type-17 precommitted CD8+ T cells

“…28,29 No significant variation in the proportions of CD161 ϩϩ , CD161 ϩ , and CD161 Ϫ cell populations was observed after culture ( Figure 7A). We found even without the addition of exogenous cytokines, by day 1 a CD8␤ low population is observed in all CD161 subsets ( ϩϩ , ϩ , and Ϫ ), which persists out to day 7 of culture ( Figure 7B).…”

“…However, they are consistent with murine data that suggest CD8␣␣ can be co-expressed on conventionally selected CD4, CD8␣␤ and DN T cells. 16,28,29,36,37 Culture experiments here used CD8 enriched PBMCs and so we are unable to comment on the possibility of induction of CD8␣␣ on CD4 and DN T cells in humans under similar experimental conditions. Given the existing mouse data, it will be important to look for these among gutderived lymphocytes in man.…”