Jointly discovered by Bernhard Moser and Martin Lipp in 2000, “follicular B helper T cells” or T follicular helper cells (TFH) revolutionized the field of T cell immunology by challenging the binary TH1/TH2 paradigm of helper T cell identity. The subsequent identification of B cell lymphoma (Bcl)-6 as the transcriptional architect of TFH cell fate led to their formal recognition as a distinct helper T cell subset. TFH cells interact dynamically with germinal center (GC) B cells and foster proliferation and survival of B cells within the GC on the basis of high affinity for antigen. Cognate help from TFH cells is vital for GC reactions and drives the establishment of long-lived humoral immunity. This specialized function of TFH cells makes them highly significant in HIV where vaccine-mediated induction of broadly neutralizing and persistent antibody is the major goal of current HIV vaccine strategies. There are several gaps in our knowledge of TFH cell biology that need to be addressed in order to optimally harness TFH cell help to advance HIV vaccine design and to improve infection outcomes. The goal of “CD4 TFH cells in HIV” is to provide a platform to explore and communicate these rapidly evolving and highly integrated issues central to our understanding of TFH cells in HIV. We encourage reviews, perspectives, and the discussion of new concepts, hypotheses, and conflicting viewpoints. We welcome submissions on the following topics:

(1) TFH cells in peripheral blood: surrogate for GC reactions? Following vaccination or infection, activated CXCR5+ CD4 T cells transiently accumulate in peripheral blood. Are these blood effector TFH cells reliable indicators of ongoing germinal center responses in complex systems? This is an important question in humans and in rhesus macaque models of HIV where lymph node sampling is not feasible. Understanding the significance of blood TFH cells and developing assays to quantitate vaccine-specific TFH cells in blood during effector and memory time points will spearhead their utility as biomarkers of vaccine efficacy.

(2) Mucosal TFH cells: friend or foe? Generation of potent and durable antibody at the mucosal frontlines is crucial for an effective HIV vaccine. However, the TFH cell response to vaccination and infection within the mucosa is poorly understood. What is the role of vaccine-elicited TFH cells in the development of mucosal antibody? On the other hand, vaccine-elicited mucosal TFH cells may serve as targets for viral entry and thereby subvert vaccine efficacy. The development of an effective HIV vaccine will require the precise understanding of cues driving mucosal TFH cell responses their roles in vaccine efficacy.

(3) Magnitude of TFH cell response: can there be too much of a good thing? While there is strong interest in the induction of robust TFH cell responses to vaccination, there is little experimental evidence demonstrating that higher magnitude TFH cell response induces higher affinity antibody. Because selective TFH cell help forms the basis of selection and survival of high affinity B cells within the GC, could abundance of TFH cell help compromise generation of high affinity antibody?

(4) T follicular regulatory cells: important parameter of vaccine efficacy? Follicular regulatory cells (TFR) are a newly defined subset of TFH cells that suppress humoral immunity. A better understanding of their roles in vaccine-elicited humoral immune response and whether inhibiting TFR represents a strategy to enhance vaccine efficacy is a key issue in HIV vaccine design.

(5) Memory TFH cells: determinant of the efficacy of booster immunizations? Repeated vaccination in the form of prime-boost immunizations is critical in establishing strong cellular and humoral immunity against HIV. Therefore, understanding the factors facilitating the induction of memory TFH cells, and delineating how the magnitude and phenotype of vaccine-elicited memory TFH cells drives potency of the antibody recall response is critical. Equally important is understanding whether vaccine-induced memory TFH cells provide a fertile target for viral entry and replication upon HIV exposure.

(6) Role of TFH cells in acute HIV infection: mechanisms of permissivity to HIV and consequences for bNab development What are the cell-intrinsic mechanisms driving HIV entry and replication within GC TFH cells, and does their residence within GCs, typically restricted from cytolytic CD8 T cell influx, foster establishment of viral reservoirs? Importantly, how does viral replication in TFH cells impact their ability to provide B cell help and induce bNAbs? These issues lie at the crux of deciphering the role of TFH cells in HIV infection.

(7) Role of TFH cells in chronic HIV infection: how does antigen persistence influence the GC response? During natural infection, in some infected individuals, broadly neutralizing antibodies that have acquired extensive hypermutation and even deletion/insertion mutations do not appear until several years following initial infection. Does the duration/persistence of the TFH response influence the selection process of these unusual antibodies over long-periods of time? How do the phenotype, function, and transcriptional signature of “persistent” TFH cells differ from that of effector and memory TFH cells? Do these cells persist under anti-retroviral therapy or in chronic asymptomatic HIV infection?

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