Dendritic cell-expressed common gamma-chain recruits IL-15 for trans-presentation at the murine immunological synapse.

Beilin, Chiara; Choudhuri, Kaushik; Bouma, Gerben; Malinova, Dessislava; Llodra Gonzalez, Jaime Andrés; Stokes, David L; Shimaoka, Motumu; Springer, Timothy A; Dustin, Michael L; Thrasher, Adrian J; Burns, Siobhan O (2018). Dendritic cell-expressed common gamma-chain recruits IL-15 for trans-presentation at the murine immunological synapse. Wellcome open research, 3(84), p. 84. Wellcome Trust 10.12688/wellcomeopenres.14493.2

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Mutations of the common cytokine receptor gamma chain (γc) cause Severe Combined Immunodeficiency characterized by absent T and NK cell development. Although stem cell therapy restores these lineages, residual immune defects are observed that may result from selective persistence of γc-deficiency in myeloid lineages. However, little is known about the contribution of myeloid-expressed γc to protective immune responses.  Here we examine the importance of γc for myeloid dendritic cell (DC) function. We utilize a combination of DC/T-cell co-culture assays and a novel lipid bilayer system mimicking the T cell surface to delineate the role of DC-expressed γc during DC/T-cell interaction. We observed that γc in DC was recruited to the contact interface following MHCII ligation, and promoted IL-15Rα colocalization with engaged MHCII. Unexpectedly, trans-presentation of IL-15 was required for optimal CD4+T cell activation by DC and depended on DC γc expression. Neither recruitment of IL-15Rα nor IL-15 trans-signaling at the DC immune synapse (IS), required γc signaling in DC, suggesting that γc facilitates IL-15 transpresentation through induced intermolecular associations or cytoskeletal reorganization following MHCII ligation. These findings show that DC-expressed γc is required for effective antigen-induced CD4+ T cell activation. We reveal a novel mechanism for recruitment of DC IL-15/IL-15Rα complexes to the IS, leading to CD4+ T cell costimulation through localized IL-15 transpresentation that is coordinated with antigen-recognition.

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