Interleukin-2 regulates CC chemokine receptor expression and chemotactic responsiveness in T lymphocytes.

TLDR

CC chemokines attract T lymphocytes, with memory phenotype CD45RO+ cells considered the main responders, yet studies have produced contradictory results and the influence of lymphocyte activation and proliferation remains unclear. The authors cultured CD45RO+ blood lymphocytes under various stimulatory conditions to assess chemotaxis and chemokine receptor expression. IL‑2 is essential for up‑regulating CC‑CKR1 and CC‑CKR2 on CD45RO+ T cells and for their chemotaxis toward CC chemokines; removal of IL‑2 rapidly suppresses receptor expression and migration, while re‑addition restores them, and although IL‑4, IL‑10, and IL‑12 partially mimic this effect, activation through TCR/CD3 and CD28 actually down‑regulates the receptors even in the presence of IL‑2, whereas IL‑2 does not induce CXC receptors or IL‑8 chemotaxis, indicating that IL‑2‑mediated expansion is required for antigen‑activated T‑cell recruitment to inflammatory sites.

Abstract

Several studies have shown that CC chemokines attract T lymphocytes, and that CD45RO+, memory phenotype cells are considered to be the main responders. The results, however, have often been contradictory and the role of lymphocyte activation and proliferation has remained unclear. Using CD45RO+ blood lymphocytes cultured under different stimulatory conditions, we have now studied chemotaxis as well as chemokine receptor expression. Expression of the RANTES/MIP-1 alpha receptor (CC-CKR1) and the MCP-1 receptor (CC-CKR2) was highly correlated with migration toward RANTES, MCP-1, and other CC chemokines, and was strictly dependent on the presence of IL-2 in the culture medium. Migration and receptor expression were rapidly downregulated when IL-2 was withdrawn, but were fully restored when IL-2 was added again. The effect of IL-2 could be partially mimicked by IL-4, IL-10, or IL-12, but not by IL-13, IFN gamma, IL-1 beta, TNF-alpha, or by exposure to anti-CD3, anti-CD28 or phytohemagglutinin. Activation of fully responsive lymphocytes through the TCR/CD3 complex and CD28 antigen actually had the opposite effect. It rapidly downregulated receptor expression and consequent migration even in the presence of IL-2. In contrast to the effects on CC chemokine receptors, stimulation of CD45RO+ T lymphocytes with IL-2 neither induced the expression of the CXC chemokine receptors, IL8-R1 and IL8-R2, nor chemotaxis to IL-8. The prominent role of IL-2 in CC chemokine responsiveness of lymphocytes suggests that IL-2-mediated expansion is a prerequisite for the recruitment of antigen-activated T cells into sites of immune and inflammatory reactions.