Reversible Reprogramming of Circulating Memory T Follicular Helper Cell Function during Chronic HIV Infection.

TitleReversible Reprogramming of Circulating Memory T Follicular Helper Cell Function during Chronic HIV Infection.
Publication TypeJournal Article
Year of Publication2015
AuthorsCubas R, van Grevenynghe J, Wills S, Kardava L, Santich BH, Buckner CM, Muir R, Tardif V, Nichols C, Procopio F, He Z, Metcalf T, Ghneim K, Locci M, Ancuta P, Routy J-P, Trautmann L, Li Y, McDermott AB, Koup RA, Petrovas C, Migueles SA, Connors M, Tomaras GD, Moir S, Crotty S, Haddad EK
JournalJ Immunol
Volume195
Issue12
Pagination5625-36
Date Published12/15/2015
ISSN1550-6606
Abstract

Despite the overwhelming benefits of antiretroviral therapy (ART) in curtailing viral load in HIV-infected individuals, ART does not fully restore cellular and humoral immunity. HIV-infected individuals under ART show reduced responses to vaccination and infections and are unable to mount an effective antiviral immune response upon ART cessation. Many factors contribute to these defects, including persistent inflammation, especially in lymphoid tissues, where T follicular helper (Tfh) cells instruct and help B cells launch an effective humoral immune response. In this study we investigated the phenotype and function of circulating memory Tfh cells as a surrogate of Tfh cells in lymph nodes and found significant impairment of this cell population in chronically HIV-infected individuals, leading to reduced B cell responses. We further show that these aberrant memory Tfh cells exhibit an IL-2-responsive gene signature and are more polarized toward a Th1 phenotype. Treatment of functional memory Tfh cells with IL-2 was able to recapitulate the detrimental reprogramming. Importantly, this defect was reversible, as interfering with the IL-2 signaling pathway helped reverse the abnormal differentiation and improved Ab responses. Thus, reversible reprogramming of memory Tfh cells in HIV-infected individuals could be used to enhance Ab responses. Altered microenvironmental conditions in lymphoid tissues leading to altered Tfh cell differentiation could provide one explanation for the poor responsiveness of HIV-infected individuals to new Ags. This explanation has important implications for the development of therapeutic interventions to enhance HIV- and vaccine-mediated Ab responses in patients under ART.

DOI10.4049/jimmunol.1501524
Alternate JournalJ. Immunol.
PubMed ID26546609
PubMed Central IDPMC4670798
Grant List103230 / / Canadian Institutes of Health Research / Canada
1R01AI106482-01AI / AI / NIAID NIH HHS / United States
AI064518 / AI / NIAID NIH HHS / United States
P01 AI104722 / AI / NIAID NIH HHS / United States
P30AI36214 / AI / NIAID NIH HHS / United States
R01 AI102766 / AI / NIAID NIH HHS / United States
R01 AI106482 / AI / NIAID NIH HHS / United States
R01AI102766 / AI / NIAID NIH HHS / United States
T32 AI052077 / AI / NIAID NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
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