In HIV-positive patients, myeloid-derived suppressor cells induce T-cell anergy by suppressing CD3[zeta] expression through ELF-1 inhibition

Objective: During HIV infection, a down-modulation of CD3[zeta] 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 CD3[zeta] expression. Moreover, we investigated the mechanisms of CD3[zeta] decrease exploited by MDSC. Design and method: CD3[zeta] 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 CD3[zeta] 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 super(+) T-cell count below 400cells/[mu]l. We found an inverse correlation between the percentage of Gr-MDSC and CD3[zeta] level. Moreover, in-vitro MDSC depletion induced the up-regulation of CD3[zeta] in T cells, restoring the functionality of [alpha][beta], but not [gamma][delta] T cells. The in-vitro effect of isolated MDSC on CD3[zeta] expression was found cell contact-dependent, and was not mediated by previously described molecules. CD3[zeta] 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.