ITK and IL-15 support two distinct subsets of CD8+T cells

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Abstract
CD8+T cells are commonly divided into naïve CD44loCD122loand “memory phenotype” CD44hiCD122hicells. Here we show data suggesting that these two cell populations represent independent CD8+T cell subsets. Whereas IL-15−/−mice lack CD44hiCD122hiCD8+T cells, mice deficient in the kinase ITK lack CD44loCD122locells among CD8+T cells. The same defects were observed during thymus development. CD44hiCD122hicells were found among double-positive thymocytes and increased in frequency during CD8 development in wild-type mice. At the mature stage, IL-15−/−mice harbored virtually no CD44hiCD122hiCD8+thymocytes. In contrast, ITK−/−mice lacked CD44loCD122loCD8+cells at this stage. We generated mice with genetic deletions in both IL-15 and ITK and observed a severe reduction of all CD8+T cells. The two CD44loCD122loand CD44hiCD122hiCD8+T cell subsets differed in the periphery in that natural killer (NK) receptor expression was found only on CD44hiCD122hiCD8+T cells. This expression was paralleled by their ability to respond to both T cell receptor and NK receptor engagements. In contrast, CD44loCD122loCD8+T cells mounted stronger responses to T cell receptor stimulation but failed to recognize NK receptor ligands. Thus, whereas ITK-dependent CD44loCD122loCD8+T cells appear to represent conventional CD8+T cells, IL-15-dependent CD44hiCD122hiCD8+T cells may have functions in both adaptive and innate immunity.