The interaction of LCK and the CD4 co-receptor alters the dose response of T-cells to interleukin-7

CD8 and CD4 T-cells grow optimally under different concentrations of the cytokine, interleukin-7 (IL-7). While CD8 T-cells expand at high doses of IL-7, CD4 T-cells favor low doses. To examine the reason for the preference of CD4 T-cells for lower doses of the cytokine, we used IL-7 dependent T-cells to study signal transduction upon a range of IL-7 concentrations. We found that the high dose responsiveness of CD8 T-cells to IL-7 could be altered if these cells also expressed CD4. Using the phosphorylation of STAT5 as an indicator of growth, we found that the co-receptor associated kinase, LCK, contributed to phospho-STAT5 levels. Phospho-STAT5 was elevated at high dose IL-7 for CD8 T-cells and at low dose IL-7 for CD4 T-cells, which was reversed upon LCK inhibition. Examining the direct association of LCK with CD4 using a T- cell line that over-expresses CD4, we determined that CD4 could directly sequester LCK. Non-CD4 T-cells were not restricted in this manner and levels of phospho-STAT5 increased proportionally to the IL-7 dose. Our studies, therefore, show that the response of a T-cell to IL-7 can be modulated by the availability of LCK.