Abstract
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.
Highlights
Follicular helper CD4 T cells (TFH) are crucial for the development of antigen-specific B cells within germinal centers (GC)
We characterize peripheral TFH cells and show that unlike TFH cells, peripheral TFH cells secrete a diverse array of cytokines and decrease, rather than increase, during chronic HIV infection
We did not observe a relationship between peripheral TFH cells and memory B cells, or with the production of neutralizing antibodies to HIV
Summary
Follicular helper CD4 T cells (TFH) are crucial for the development of antigen-specific B cells within germinal centers (GC). Phenotypic and gene signature analysis has revealed a highly conserved molecular profile of TFH cells in humans, nonhuman primates (NHP) and mice, which is characterized by increased expression of Bcl-6, CXCR5, PD-1, ICOS and decreased expression of CCR7 [2,3,4]. Human TFH cells exhibit a polarized cytokine profile characterized by compromised production of TH1 cytokines and increased secretion of IL-4, IL-10 and IL-21 [5]. We have recently shown that NHP GC-TFH display compromised in vivo cell cycling and are prone to in vitro cell death [4]. TFH cells may adopt a ‘‘central memory’’ phenotype or undergo cell death after the effector phase [13].
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