In HIV+ patients, Myeloid Derived Suppressor Cells induce T cell anergy by suppressing CD3ζ expression through ELF-1 inhibition

The CD3ζ chain is indispensable for coupling antigen recognition to T cell response. During HIV infection, a down-modulation of CD3ζ was found on T cells, contributing to T cell anergy. It has been shown that circulating myeloid derived suppressor cells (MDSC) are elevated in HIV+ patients, and correlate with disease progression. In this work, we studied the correlation between MDSC frequency and T cell CD3ζ expression. Moreover, we investigated the mechanisms of CD3ζ decrease exploited by MDSC. CD3ζ expression and MDSC frequency were evaluated by flow cytometry on PBMC from 105 HIV+ patients. We found that granulocytic-MDSC (Gr-MDSC) were expanded in HIV+ patients compared to healthy donors; in particular, 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 Gr-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 Gr-MDSC on CD3ζ expression was found cell contact-dependent, and was not mediated by previously described molecules. CD3ζ downmodulation corresponds to the decrease of its mRNA induced by silencing the transcription factor ELF-1.