CD28 co-stimulation results in down-regulation of lymphotactin expression in human CD4(+) but not CD8(+) T cells via an IL-2-dependent mechanism

Chemokines ave key molecules in promoting leukocyte migration and, for some of them, T cell adhesion and activation. Lymphotactin, which is the unique known member of the C class of chemokines, is produced by and acts on T ly mphocytes, but the requirement of costimulatory pathways such as CD28 for i ts expression is largely unknown. CD28 plays a dominant role in the amplifi cation of T cell proliferation, survival and cytokine production. In this r eport, we demonstrate that human lymphotactin expression, at both the mRNA and protein levels, is optimally induced by CD3/TCR activation alone, where as CD28 costimulation turns off this expression. This down-regulation is no t attributable to secondary activation via CTLA-4, the alternative counter- receptor of B7 ligands. Only the CD4(+) and not the CD8(+) subset is direct ly affected by this negative regulation. Transcript destabilization can be ruled out as a mechanism by which CD28 down-regulates lymphotactin expressi on. However, such down-regulation can be partly induced by IL-2 and abrogat ed by blocking IL-2/IL-2 receptor interaction. This particular profile of l ymphotactin expression is not in line with the prevailing dogma of up-regul ation of cytokine gene expression by CD28 costimulation, and represents a n ew CD28-mediated regulatory mechanism for lymphotactin expression.