X-linked Severe Combined Immunodeficiency (X-SCID) caused by mutations in the
common cytokine receptor γ chain (γc) is a fatal disease in which the immune system
is severely compromised as T and NK cells are absent or profoundly diminished.
Although dendritic cells (DCs) are key antigen presenting cells and are crucial for
the induction of normal immune responses, little is known about their function in this
disease. This is of specific importance as the myeloid compartment, including DCs,
frequently remains of host origin, and therefore γc-deficient, after bone marrow
transplant or gene therapy for this form of SCID. Curiously, even after curative
treatment, patients with X-SCID continue to have a long-term susceptibility to
human papilloma virus infection. We hypothesised that this could be due to
persistent myeloid defects.
Using a murine model of X-SCID, we demonstrated that, in the absence of functional
γc, DCs are less efficient at priming antigen-specific responses in γc-expressing
CD4+ T cells. Despite the widely held view that IL-15Rα is the chain responsible for
IL-15 transpresentation to NK and CD8+ T cells, here we have shown that
expression of the γc by DCs is necessary for effective transpresentation to CD4+ T
cells. In a novel system of supported planar bilayers mimicking the T cell interface,
we demonstrated that DC-expressed γc colocalises with MHC II clusters and
mediates IL-15Rα recruitment to the immunological synapse (IS). This depended on
simultaneous TCR engagement with MHC-bound antigen, suggesting that IL-15
transpresentation may have important costimulatory function for T cell activation.
Altogether, these data indicate that γc-deficiency impairs DC functions and reveal a
novel mechanism for recruitment or stabilization of DC IL-15/IL-15Rα complexes at
the IS leading to localized transpresentation of IL-15. The contribution of myeloid
γc-deficiency to persistent immunodeficiency in transplanted X-SCID patients
warrants further investigation