In HIV-positive patients, myeloid-derived suppressor cells induce T-cell anergy by suppressing CD3ζ expression through ELF-1 inhibition

OBJECTIVE: During HIV infection, a down-modulation of CD3ζ was found on T cells, contributing to T-cell anergy. In this work, we studied the correlation between myeloid-derived suppressor cells (MDSC) frequency and T-cell CD3ζ expression. Moreover, we investigated the mechanisms of CD3ζ decrease exploited by MDSC. DESIGN AND METHOD: CD3ζ expression and MDSC frequency were evaluated by flow cytometry on peripheral blood mononuclear cells from 105 HIV-positive (HIV+) patients. The role of MDSC in the modulation of the HIV-specific T-cell response was evaluated. The level of CD3ζ mRNA and ELF-1 protein were analysed by real-time-PCR and western blot, respectively. RESULTS: We found that granulocytic-MDSC (Gr-MDSC) were expanded in HIV+ patients compared with healthy donors; in particular, in cART-treated individuals a higher Gr-MDSC frequency was observed in patients with a CD4 T-cell count below 400 cells/μl. We found an inverse correlation between the percentage of Gr-MDSC and CD3ζ level. Moreover, in-vitro MDSC depletion induced the up-regulation of CD3ζ in T cells, restoring the functionality of αβ, but not γδ T cells. The in-vitro effect of isolated MDSC on CD3ζ expression was found cell contact-dependent, and was not mediated by previously described molecules. CD3ζ down-modulation corresponds to the decrease of its mRNA induced by silencing the transcription factor ELF-1. CONCLUSION: Our data provide new knowledge on mechanisms used by Gr-MDSC in immune-modulation and on their role in the immune reconstitution during antiviral treatments.