Abstract
Background: 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. Methods: We utilize a combination of in vitro 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. Results: 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 cis associations or cytoskeletal reorganization following MHCII ligation. Conclusions: 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.
Highlights
Severe Combined Immunodeficiency (SCID) caused by deficiency of the common cytokine receptor gamma chain is characterized by defective T and NK cell development, resulting in lifethreatening infections
Patients with γc-deficient SCID remain susceptible to opportunistic human papilloma virus (HPV) infections even when T cell function is restored by bone marrow transplantation (BMT)
This raises the possibility that residual γc-deficient dendritic cell (DC), which persist in the absence of myeloablative conditioning, might be ineffective in priming T cell immunity
Summary
Severe Combined Immunodeficiency (SCID) caused by deficiency of the common cytokine receptor gamma chain (γc) is characterized by defective T and NK cell development, resulting in lifethreatening infections. As many SCID patients receive BMT without any chemotherapy conditioning, B cell and myeloid lineages remain of host origin and γc-deficient in the majority of cases[1,2] This includes antigen-presenting dendritic cells (DC) derived from bone marrow, such as dermal (migratory) DC4 and those that selfrenew in tissues, such as epidermal Langerhans cells (LC). We show that γc-deficiency in DC critically impairs IL-15Rα recruitment and IL-15 transpresentation to naïve CD4+ T cells at the immunological synapse, resulting in incomplete T cell activation In light of these findings, we suggest a novel model for IL-15 transpresentation in which the DC-IS regulates co-stimulation of CD4+ T-cells during antigendependent priming
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