Comprehensive analysis of frequency and phenotype of T regulatory cells in HIV infection: CD39 expression of FoxP3+ T regulatory cells correlates with progressive disease.
There are conflicting data about the frequency and role of regulatory T cells (Tregs) during the course of HIV infection. Peripheral blood of a large cohort of HIV-infected patients (n = 131) at different stages of disease, including 15 long-term nonprogressors and 21 elite controllers, was analyzed to determine the frequency and phenotype of Tregs, defined as CD4(+), CD25(high), CD127(low), FoxP3(high) cells. A significantly increased relative frequency of Tregs within the CD4(+) compartment of HIV(+) patients compared to that of healthy controls (P < 0.0001) was observed. Additionally, the relative frequency of Tregs directly correlated with HIV viral load and inversely with CD4(+) counts. However, the absolute Treg number was reduced in HIV-infected patients versus healthy controls (P < 0.0001), with the exception of elite controllers (P > 0.05). The loss of absolute Treg numbers coincided with rising markers of immune activation (P < 0.0006). The initiation of antiviral therapy significantly increased absolute Treg numbers (P < 0.0031). We find that the expression of CD39, a newly defined ectonucleotidase with immunomodulatory functions on Tregs, correlated with progressive HIV disease, HIV viral load, and immune activation. Of note, when tested in peripheral blood mononuclear cells of healthy volunteers, the in vitro capacity to suppress T-cell proliferation was limited to CD4(+), CD25(high), CD39(+) T cells. Interestingly, Tregs of elite controllers exhibited not only the highest expression of CCR5, CTLA-4, and ICOS but also the lowest level of CD39. The data presented here reconcile the seemingly contradictory results of previous studies looking at Tregs in HIV and highlight the complexity of Treg-mediated immunoregulation during human viral infections.
Infectious Disease Unit, Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. julianszw@gmail.com
Julian
J
Schulze Zur Wiesch
Adriana
A
Thomssen
Philip
P
Hartjen
Ilona
I
Tóth
Clara
C
Lehmann
Dirk
D
Meyer-Olson
Kristina
K
Colberg
Sebastian
S
Frerk
Dalia
D
Babikir
Stefan
S
Schmiedel
Olaf
O
Degen
Stefan
S
Mauss
Jürgen
J
Rockstroh
Schlomo
S
Staszewski
Pavel
P
Khaykin
Alexander
A
Strasak
Ansgar W
AW
Lohse
Gerd
G
Fätkenheuer
Joachim
J
Hauber
Jan
J
van Lunzen
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000032:analysis*; D001081:Apyrase / Q000032:analysis*; D018450:Disease Progression; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis*; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000276:immunology*; D019562:Viral Load
D015703:Antigens, CD; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D001081:Apyrase; C067869:CD39 antigen