GM-CSF regulation of autophagy in monocytes enhances immune response to Cryptococcus gattii

Abstract

Abstract Cryptococcal meningoencephalitis is responsible for over 15% of HIV-related deaths worldwide and is also the most common cause of non-viral meningitis in the US. The role of T-cells in cryptococcal disease is well studied however a significant portion of previously healthy non-HIV patients with cryptococcal meningoencephalitis have an intact CD4+ T-cell compartment. We observed that patients with GM-CSF autoantibodies have a decrease in autophagy within their classical monocyte compartment. This reduction in autophagy is correlated with an enhancement of IL-1β production, additionally GM-CSF synergizes with TLR2, TLR4, and TLR5 in the induction of IL-1β. The importance of GM-CSF inhibition of autophagy appears to be most dramatic when monocytes are in conditions of weak TLR stimulation, particularly TLR4 stimulation with LPS. The capsule for Cryptococcus gattii, the prominent species involved with cryptococcal meningoencephalitis in previously health adults, has been shown to have the ability to dampen or block surface recognition by the immune system, thus GM-CSF synergy may have a critical role for driving the immune response against C. gattii infection. In the murine model of myeloid-specific ATG5 deficiency, mice have enhanced survival to C. gattii infection. Additionally, this GM-CSF down-regulation of autophagy is independent of mTOR activity, and contingent on a cyclic AMP/CTLA4/DCP2 pathway.