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.


METHODS
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.


CONCLUSIONS
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.
aCellular Immunology Laboratory bVirology Laboratory, 'Lazzaro Spallanzani' National Institute for Infectious Diseases cImmunology and General Pathology Laboratory, Department of Biology, 'Tor Vergata' University, Rome, Italy.
Nicola
N
Tumino
Federica
F
Turchi
Silvia
S
Meschi
Eleonora
E
Lalle
Veronica
V
Bordoni
Rita
R
Casetti
Chiara
C
Agrati
Eleonora
E
Cimini
Carla
C
Montesano
Vittorio
V
Colizzi
Federico
F
Martini
Alessandra
A
Sacchi
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D017252:CD3 Complex / Q000096:biosynthesis*; D017635:Clonal Anergy; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000473:pathology*; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism*; D055815:Young Adult
D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; C512897:ELF1 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors