A role for interleukin-2 trans-presentation in dendritic cell–mediated T cell activation in humans, as revealed by daclizumab therapy

Abstract

While previous studies have described CD25 expression on mature dendritic cells (mDCs) and their production of IL-2, it remains unclear how these molecules participate in the activation of T cells. In search of the mechanisms by which daclizumab, a humanized monoclonal antibody against CD25, inhibits brain inflammation in multiple sclerosis (MS), we observed that while the drug has limited effect on polyclonal T cell activation, it potently inhibits activation of antigen (Ag)-specific T cells by mDCs. We demonstrate that in an Ag-specific manner, mDCs (and Ag-experienced T cells) secrete IL-2 to the mDC-T cell interface and mDCs “lend” their CD25 to primed T cells in trans, in order to facilitate early high affinity IL-2 signaling, which is critical for subsequent T cell expansion and development of Ag-specific effectors. Our data reveal a novel mechanism for the IL-2 receptor system in DC-mediated activation of T cells.

CNS vasculitis in a patient with MS on daclizumab monotherapy

“…9 We believe that this latter effect underlies the therapeutic efficacy of daclizumab in ZAP10. For this new mechanism to operate, daclizumab needs to be administered in concentrations that saturate IL-2Ra in the lymph nodes.…”

“…For this new mechanism to operate, daclizumab needs to be administered in concentrations that saturate IL-2Ra in the lymph nodes. 9 Conversely, when daclizumab concentrations fall below saturating levels in the lymphatic tissues, but still saturate CD25 in the blood, then de novo activated T cells that upregulate CD25 upon antigen-specific stimulation will experience CD25 blockade only during their transit in blood. Such late inhibition of high-affinity IL-2 signaling will make effector T cells resistant to activation-induced cell death, leading to paradoxically greater expansion and survival of antigen-specific T cells.…”

“…Such late inhibition of high-affinity IL-2 signaling will make effector T cells resistant to activation-induced cell death, leading to paradoxically greater expansion and survival of antigen-specific T cells. 9 It is conceivable that the 8-week interruption in daclizumab dosing in ZAP10 created such a vulnerable situation. Furthermore, the decline in T-regs, experienced in absence of normal expansion of CD56 bright NK cells, may have left this patient uniquely defenseless to de novo activation of the adaptive immune responses by unknown trigger.…”

Pharmacodynamic effects of daclizumab in the intrathecal compartment

“…As daclizumab limits consumption of IL‐2 by T cells14 without limiting the ability of activated T cells or dendritic cells to secrete IL‐2,15 we predicted that daclizumab therapy should lead to increased IL‐2 levels in biological fluids. However, this prediction was difficult to prove because the levels of IL‐2 were below the detection limits of standard immunoassays.…”

“…This interpretation is supported by the fact that we observed only trend, which did not reach statistical significance, for systemic (i.e., serum) inhibition of CHIT3L1 levels upon initiation of daclizumab therapy, with no significant correlations between two compartments (data not shown). On the other hand, daclizumab may exert inhibitory effects on activated macrophages, which express CD25 during activation, and it also limits the ability of myeloid DCs to present antigens in immunostimulatory manner 15. Consequently, whether the activated myeloid lineage drives MS pathology or is an epiphenomenon cannot be determined without therapy that strongly inhibits either myeloid lineage or demyelination and ability to measure its efficacy in vivo.…”