Retroviral b-Zip protein (HBZ) contributes to the release of solubleand exosomal immune checkpoint molecules in the context ofneuroinflammation

by | Sep 24, 2023 | Publications


HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic,progressive, neuroinflammatory demyelinating condition of the spinal cord. Wehave previously shown that aberrant expression and activity of immune check-point (ICP) molecules such as PD-1 and PD-L1/PD-L2, negatively associates withthe cytolytic potential of T cells in individuals with HAM/TSP. Interestingly, ICPscan exist in a soluble cell-free form and can be carried on extracellular vesicles(EVs) and exosomes (small EVs,<300 nm) while maintaining their immunomod-ulatoryactivity.Therefore,weinvestigatedtheroleofsolubleandexosomalICPsin HTLV-1 associated neuroinflammation. For the very first time, we demonstrate aunique elevated presence of several stimulatory (CD27, CD28, 4-1BB) and inhibitory(BTLA, CTLA-4, LAG-3, PD-1, PD-L2) ICP receptors in HAM/TSP sera, and in puri-fied exosomes from a HAM/TSP-derived HTLV-1-producing (OSP2) cells. TheseICPs were found to be co-localized with the endosomal sorting complex requiredfor transport (ESCRT) pathway proteins and exhibited functional binding withtheir respective ligands. Viral proteins and cytokines (primarily IFNγ)werefoundto be present in purified exosomes. IFNγexposureenhancedthereleaseofICPmolecules while antiretroviral drugs (Azidothymidine and Lopinavir) significantlyinhibited this process. HTLV-1 b-Zip protein (HBZ) has been linked to factors thatenhance EV release and concurrent knockdown here led to the reduced expressionof ESCRT associated genes (e.g.,Hrs,Vsp, Alix, Tsg)aswellasabrogatedtherelease of ICP molecules, suggesting HBZ involvement in this process. Moreso, exo-somes from OSP2 cells adversely affected CD8 T-cell functions by diminishing levelsof cytokines and cytotoxic factors. Collectively, these findings highlight exosome-mediated immunomodulation of T-cell functions with HBZ and ESCRT pathwaysas an underlying mechanism in the context of HTLV-1-induced neuroinflammation.

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