'Bystander polarization' of CD4+ T cells:: activation with high-dose IL-2 renders naive T cells responsive to IL-12 and/or IL-18 in the absence of TCR ligation

Responsiveness of CD4(+) T cells to the IFN-gamma-inducing cytokines IL-12 and IL-18 is generally thought to be acquired only after stimulation via the TCR. We report herein that stimulation of naive CD4+ T cells with high-dose IL-2 (1000 U/ml) renders these cells responsive to IL-12 and/or IL-18 without a requirement for TCR ligation. Naive CD4(+)CD62L(+) T cells from normal C57BL/6 mice or from DO11.10/Rag2(-/-) OVA-specific TCR-transgenic mice secreted substantial amounts of IFN-gamma when stimulated concurrently with high-dose IL-2 plus IL-12 or IL-18. mRNA encoding both chains of the IL-12 and the IL-18 receptors was expressed by CD4(+) T cells after stimulation with high-dose IL-2. Furthermore, anti-CD3-induced IL-12/IL-18 responsiveness was fully abrogated in the presence of cyclosporin A whereas IL-2-induced IL-12/IL-18 responsiveness was not, reminiscent of the previously reported IL-12(+)IL-18 innate pathway of T cell activation. Lastly, after stimulation with IL-2+IL-12, naive CD4(+) T cells from DO11.10/Rag2(-/-) mice exhibited polarization towards a Th1 phenotype (high IFN-gamma but no IL-4) during secondary stimulation with immobilized anti-CD3. We have coined the term 'bystander polarization' to describe this phenomenon and we speculate that bystander polarization of naive CD4(+) T cells may occur in vivo during strong antigen-specific immune responses.