An overview of the role of iron in T cell activation

Iron, an essential growth trace element, is required for proliferation of all living cells, including T lymphocytes. Many, though not all, immune responses require lymphocyte proliferation. Iron deficiency, a worldwide public health problem for children and for women of childbearing age, is associated with impaired lymphocyte proliferative responses to mitogens and cell-mediated immunity. However, the mechanisms have not been fully elucidated. Our data on certain early key events in the T cell activation pathways, obtained from iron-deficient murine splenic T lymphocytes, show reductions in hydrolysis of cell membrane phosphatidyl inositol 4,5 bisphosphate, protein kinase C activation, and interleukin-2 secretion. Although the expression of CD3 molecule (a component of the T cell-receptor/CD3 complex, required for T cell activation) is not decreased by iron deficiency in splenocytes and thymocytes, the expression of the co-stimulatory molecule, CD28, is. Iron-deficiency increases the percentage of CD3+/CD28- thymocytes but decreases that of CD3-/CD28+ cells. Iron deficiency and iron chelation by deferoxamine decrease CD28 fluorescence intensity but tends to increase that of CD3. Progression of activated spleen cells through the cell cycle (Go/G1, S, G2/M phases) is also altered by iron deficiency independently of differences in the percentages of CD3+ T cells between groups, probably through impaired transition of G1 to S phase. Data suggest that the role of iron in T cell proliferation is not limited to the regulation of ribonucleotide reductase activity, but also involves other steps in the T cell activation pathways.