TY - JOUR
T1 - Loss of Circulating CD4 T Cells with B Cell Helper Function during Chronic HIV Infection
AU - Boswell, Kristin L.
AU - Paris, Robert
AU - Boritz, Eli
AU - Ambrozak, David
AU - Yamamoto, Takuya
AU - Darko, Sam
AU - Wloka, Kaska
AU - Wheatley, Adam
AU - Narpala, Sandeep
AU - McDermott, Adrian
AU - Roederer, Mario
AU - Haubrich, Richard
AU - Connors, Mark
AU - Ake, Julie
AU - Douek, Daniel C.
AU - Kim, Jerome
AU - Petrovas, Constantinos
AU - Koup, Richard A.
PY - 2014/1
Y1 - 2014/1
N2 - The interaction between follicular T helper cells (TFH) and B cells in the lymph nodes and spleen has a major impact on the development of antigen-specific B cell responses during infection or vaccination. Recent studies described a functional equivalent of these cells among circulating CD4 T cells, referred to as peripheral TFH cells. Here, we characterize the phenotype and in vitro B cell helper activity of peripheral TFH populations, as well as the effect of HIV infection on these populations. In co-culture experiments we confirmed CXCR5+ cells from HIV-uninfected donors provide help to B cells and more specifically, we identified a CCR7highCXCR5highCCR6highPD-1high CD4 T cell population that secretes IL-21 and enhances isotype-switched immunoglobulin production. This population is significantly decreased in treatment-naïve, HIV-infected individuals and can be recovered after anti-retroviral therapy. We found impaired immunoglobulin production in co-cultures from HIV-infected individuals and found no correlation between the frequency of peripheral TFH cells and memory B cells, or with neutralization activity in untreated HIV infection in our cohort. Furthermore, we found that within the peripheral TFH population, the expression level of TFH-associated genes more closely resembles a memory, non-TFH population, as opposed to a TFH population. Overall, our data identify a heterogeneous population of circulating CD4 T cells that provides in vitro help to B cells, and challenges the origin of these cells as memory TFH cells.
AB - The interaction between follicular T helper cells (TFH) and B cells in the lymph nodes and spleen has a major impact on the development of antigen-specific B cell responses during infection or vaccination. Recent studies described a functional equivalent of these cells among circulating CD4 T cells, referred to as peripheral TFH cells. Here, we characterize the phenotype and in vitro B cell helper activity of peripheral TFH populations, as well as the effect of HIV infection on these populations. In co-culture experiments we confirmed CXCR5+ cells from HIV-uninfected donors provide help to B cells and more specifically, we identified a CCR7highCXCR5highCCR6highPD-1high CD4 T cell population that secretes IL-21 and enhances isotype-switched immunoglobulin production. This population is significantly decreased in treatment-naïve, HIV-infected individuals and can be recovered after anti-retroviral therapy. We found impaired immunoglobulin production in co-cultures from HIV-infected individuals and found no correlation between the frequency of peripheral TFH cells and memory B cells, or with neutralization activity in untreated HIV infection in our cohort. Furthermore, we found that within the peripheral TFH population, the expression level of TFH-associated genes more closely resembles a memory, non-TFH population, as opposed to a TFH population. Overall, our data identify a heterogeneous population of circulating CD4 T cells that provides in vitro help to B cells, and challenges the origin of these cells as memory TFH cells.
UR - http://www.scopus.com/inward/record.url?scp=84893746319&partnerID=8YFLogxK
U2 - 10.1371/journal.ppat.1003853
DO - 10.1371/journal.ppat.1003853
M3 - Article
C2 - 24497824
AN - SCOPUS:84893746319
SN - 1553-7366
VL - 10
JO - PLoS Pathogens
JF - PLoS Pathogens
IS - 1
M1 - e1003853
ER -