TY - JOUR
T1 - Reversible reprogramming of circulating memory T follicular helper cell function during chronic HIV infection
AU - Cubas, Rafael
AU - Van Grevenynghe, Julien
AU - Wills, Saintedym
AU - Kardava, Lela
AU - Santich, Brian H.
AU - Buckner, Clarisa M.
AU - Muir, Roshell
AU - Tardif, Virginie
AU - Nichols, Carmen
AU - Procopio, Francesco
AU - He, Zhong
AU - Metcalf, Talibah
AU - Ghneim, Khader
AU - Locci, Michela
AU - Ancuta, Petronella
AU - Routy, Jean Pierre
AU - Trautmann, Lydie
AU - Li, Yuxing
AU - McDermott, Adrian B.
AU - Koup, Rick A.
AU - Petrovas, Constantinos
AU - Migueles, Steven A.
AU - Connors, Mark
AU - Tomaras, Georgia D.
AU - Moir, Susan
AU - Crotty, Shane
AU - Haddad, Elias K.
N1 - Publisher Copyright:
© 2015 The Authors.
PY - 2015/12/15
Y1 - 2015/12/15
N2 - 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 reducedBcell 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.
AB - 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 reducedBcell 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.
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U2 - 10.4049/jimmunol.1501524
DO - 10.4049/jimmunol.1501524
M3 - Article
C2 - 26546609
AN - SCOPUS:84958259928
SN - 0022-1767
VL - 195
SP - 5625
EP - 5636
JO - Journal of Immunology
JF - Journal of Immunology
IS - 12
ER -