ITK and IL-15 Support Two Distinct Subsets of CD8⁺ T Cells

CD8⁺ T cells are commonly divided into naïve $CD44^{Io}CD122^{Io}$ and "memory phenotype" $CD44^{hi}CD122^{hi}$ cells. Here we show data suggesting that these two cell populations represent independent CD8⁺ T cell subsets. Whereas $IL-15^{-/-}$ mice lack $CD44^{hi}CD122^{hi}$ CD8⁺ T cells, mice deficient in the kinase ITK lack $CD44^{Io}CD122^{Io}$ cells among CD8⁺ T cells. The same defects were observed during thymus development. $CD44^{hi}CD122^{hi}$ cells 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 $CD44^{hi}CD122^{hi}$ CD8⁺ thymocytes. In contrast, $ITK^{-/-}$ mice lacked $CD44^{Io}CD122^{Io}$ CD8⁺ 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 $CD44^{Io}CD122^{Io}$ and $CD44^{hi}CD122^{hi}$ CD8⁺ T cell subsets differed in the periphery in that natural killer (NK) receptor expression was found only on $CD44^{hi}CD122^{hi}$ CD8⁺ T cells. This expression was paralleled by their ability to respond to both T cell receptor and NK receptor engagements. In contrast, $CD44^{Io}CD122^{Io}$ CD8⁺ T cells mounted stronger responses to T cell receptor stimulation but failed to recognize NK receptor ligands. Thus, whereas ITKdependent $CD44^{Io}CD122^{Io}$ CD8⁺ T cells appear to represent conventional CD8⁺ T cells, IL-15-dependent $CD44^{hi}CD122^{hi}$ CD8⁺ T cells may have functions in both adaptive and innate immunity.