Overall, we determined that a mean of 4.5% of CD154-positive IL-21-positive cells were CCR7highCXCR5highCCR6high (Determine 4B). and spleen has a major impact on the development of antigen-specific B cell responses during contamination or vaccination. Recent studies explained a functional equivalent of these cells among circulating CD4 T cells, referred to as Mcl-1-PUMA Modulator-8 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 contamination on these populations. In co-culture experiments we confirmed CXCR5+ cells from HIV-uninfected donors provide help to B cells and more specifically, we recognized a CCR7highCXCR5highCCR6highPD-1high CD4 T cell populace that secretes IL-21 and enhances isotype-switched immunoglobulin production. This populace is usually significantly decreased in treatment-na?ve, HIV-infected individuals and can be recovered after anti-retroviral therapy. We found impaired immunoglobulin production in Mcl-1-PUMA Modulator-8 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 populace, the expression level of TFH-associated genes more closely resembles a memory, non-TFH populace, as opposed to a TFH populace. Overall, our data identify a heterogeneous populace of circulating CD4 T cells that provides help to B SFN cells, and difficulties the origin of these cells as memory TFH cells. Author Summary Follicular T helper cells (TFH) interact with B cells within germinal centers of lymphoid tissue to promote the survival, isotype switching and generation of high affinity memory B cells and plasma cells. Recently, a populace of circulating CD4 T cells that shares phenotypic and functional characteristics with TFH cells, named peripheral TFH cells, has been identified. The relationship between peripheral TFH cells in the blood and TFH cells within the lymphoid tissue remains unclear, and whether or not peripheral TFH cells can provide insight into T cell and B cell dynamics within lymphoid tissue during contamination or vaccination is not understood. Here we Mcl-1-PUMA Modulator-8 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 contamination. Furthermore, we did not observe a relationship between peripheral TFH cells and memory B cells, or with the production of neutralizing antibodies to HIV. Overall, our data indicate that while peripheral TFH cells share some characteristics with TFH cells, they may not represent a good surrogate to study T cell and B cell dynamics within lymphoid tissue. Introduction Follicular helper CD4 T cells (TFH) are crucial for the development of antigen-specific B cells within germinal centers (GC). TFH cells interact through co-stimulatory receptors and provide essential soluble factors (i.e. IL-4, IL-21) to promote the survival, isotype switching and selection of high affinity memory B cells [1]. Phenotypic and gene signature analysis has revealed a highly conserved molecular profile of TFH cells in humans, non-human primates (NHP) and mice, which is usually characterized by increased expression of Bcl-6, CXCR5, PD-1, ICOS and decreased expression of CCR7 [2]C[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]. Although IL-21 is usually characterized as a hallmark cytokine of TFH cells, other THelper subsets produce this cytokine [6]. The origin and differentiation of TFH is usually unclear, as previous studies found TFH cells can derive from TH1 or TH2 cells, or independently of other CD4 lineages [7]C[9]. However, it is well established that this transcription factor Bcl-6 regulates several molecules involved in TFH development (i.e. PD-1, IL-21R, CXCR5) [10], [11]. Similarly, the fate of TFH, particularly those in the germinal center (GC-TFH), following the effector phase of the immune response is usually unclear. We have recently shown that NHP GC-TFH display compromised cell cycling and are prone to cell death [4]. Other studies have shown that TFH can form a.