TRIM22 (Staf50) is an interferon (IFN)-inducible protein with unknown function. Recently, we identified TRIM22 as a novel p53 target gene and showed that overexpression of TRIM22 inhibits the clonogenic growth of monoblastic U937 cells. Moreover, expression of TRIM22 is high in lymphoid tissue, and levels decrease during T lymphocyte activation with CD3/CD2/CD28, suggesting that TRIM22 could exert antiproliferative effects. Here, a prominent increase in TRIM22 levels is observed during activation with interleukin-2 (IL-2) or IL-15 in contrast to the decrease observed during CD3/CD2/CD28-induced activation. However, stimulation of cells in these experiments was performed on crude T lymphocytes, allowing indirect regulation between different lymphocyte subtypes to take place. Therefore, to prevent interaction between different lymphocyte subtypes, expression of TRIM22 was examined during activation of sorted T lymphocyte subpopulations. In contrast to the marked changes of TRIM22 during activation of crude T lymphocytes, in isolated subpopulations, TRIM22 expression was not significantly affected in spite of IL-2-induced or CD3/CD2/CD28-induced activation. In addition, in contrast to the TRIM22 mouse ortholog Rpt-1, TRIM22 did not affect levels of CD25 (IL-2R alpha) mRNA. Our data suggest a more complex role for TRIM22 during T lymphocyte activation than merely as an antiproliferative factor. TRIM22 probably has an activation stage-specific role connected to the paracrine crosstalk during T lymphocyte activation.