Editors' ChoiceImmunology

Two Cells, One Receptor Complex

Science Signaling  10 May 2011:
Vol. 4, Issue 172, pp. ec129
DOI: 10.1126/scisignal.4172ec129

The interleukin-2 (IL-2) receptor (IL-2R) is a multisubunit protein composed of CD122 and CD132 (the β and γc signaling components) and CD25 (the nonsignaling α subunit). CD25 has a low affinity for IL-2, and receptor activation involves initial binding of the ligand to CD25 followed by its presentation to IL-2Rβ. In resting T cells, the signaling components of the IL-2R are present, but CD25 is not detectable; however, resting T cells can respond to IL-2. Furthermore, understanding signaling by the IL-2R has clinical implications because a function-blocking monoclonal antibody targeting CD25 (daclizumab) is used to promote immune tolerance in organ transplantation and multiple sclerosis, and genetic deletion of CD25 produces autoimmunity. Wuest et al. explored the mechanism by which daclizumab inhibited T cell proliferation and found that, when mature dendritic cells (mDCs) and T cells were cocultured, T cell proliferation was more effectively blocked by preincubating the mDCs, rather than the T cells, with the antibody. IL-2R signaling (as indicated by Stat5 phosphorylation) was detected in T cells exposed to mDCs, but incubation of the mDCs with daclizumab inhibited this response. T cells from a patient genetically deficient for CD25 proliferated in response to antigen stimulation when cocultured with mDCs positive for CD25, a response that was blocked if the mDCs were pretreated with daclizumab. The CD122 subunit of the IL-2R was not detectable in freshly isolated mDCs or dendritic cells stimulated to mature in culture, and these cells did not respond to IL-2. Activated T cells are negative for CD25 for the first 10 hours after stimulation. Visualization of IL-2 secretion showed that mDCs or T cells cultured alone produced little IL-2 but that both cells produced IL-2, when cocultured, that was preferentially released at the site of contact between the two cells. Visualization of CD25 showed that mDCs forming immune synapses were CD25 positive and that CD25 was localized at the immune synapse. Thus, the authors propose that mDCs present IL-2 to T cells prebound to the CD25 subunit, enabling the CD25-deficient T cells to respond.

S. C. Wuest, J. H. Edwan, J. F. Martin, S. Han, J. S. A. Perry, C. M Cartagena, E. Matsuura, D. Maric, T. A. Waldmann, B. Bielekova, A role for interleukin-2 trans-presentation in dendritic cell–mediated T cell activation in humans, as revealed by daclizumab therapy. Nat. Med. 17, 604–609 (2011). [PubMed]