Most likely there are multiple Tfh cell differentiation pathways and there is no single DC type responsible for priming Tfh cells. The DC type responsible for initiating Tfh cell differentiation is unknown. In the absence of IL-6 an early defect in Tfh cell differentiation is observed ( Choi et al., 2013a). Bcl6 is necessary for early CXCR5 expression in multiple models ( Choi et al., 2011 2013a Pepper et al., 2011). IL-6 signaling through IL-6 receptor (IL-6R - gp130) transiently induces Bcl6 expression by newly activated CD4 + T cells ( Nurieva et al., 2009). IL-6 is the earliest non-TCR signal involved in initiation of Tfh cell differentiation. Utilizing a range of systems it was found that TCR: major histocompatibility complex-II (MHCII) dwell time is a more accurate predictor of cell fate preference, with a nonlinear relationship ( Tubo et al., 2013), such that there was no simple relationship between TCR signal strength and Tfh cell differentiation. CD4 + T cells possessing TCRs with high affinity preferentially differentiated into Tfh cells in a pigeon cytochrome C (PCC) model ( Fazilleau et al., 2009), but not a Friend virus infection ( Ploquin et al., 2011). TCR signal strength can bias T cell differentiation in vivo ( Tubo et al., 2013), but a single naive mature T cell can give rise to multiple different differentiated effector cell types upon stimulation and proliferation, demonstrating that non-TCR and TCR signals combine to determine T cell differentiation fates. A simplified model of CD4 T cell differentiation pathways, showing transcription factors and inducing factors, highlighting apparent differences between human and mouse Tfh cell differentiation.Įarly Tfh cell differentiation (the DC priming phase) is regulated by IL-6, inducible costimulator (ICOS), IL-2, and T cell receptor (TCR) signal strength in mouse models. (b) Signals in CD4 T cell differentiation. (a) Stages of Tfh cell differentiation, highlighting roles of migration-associated molecules. 1) the CD4 + T cell follows a Th1, Th2, or Th17 cell differentiation program, including upregulation of chemokine receptors for inflammatory chemokines that will drive the effector cell to exit the lymphoid tissue and traffic to the site of infection or inflammation. If the cell instead receives Th1, Th2, or Th17 cell signals ( Fig. If the chemokine receptor CXCR5 is expressed, the early Tfh cell will migrate to the border of the B cell follicle and undergo further Tfh cell differentiation. The CD4 + T cell undergoes a cell fate decision within the first few rounds of cell division ( Choi et al., 2011 2013b). ![]() The canonical Tfh cell differentiation process starts at initial dendritic cell (DC) priming of a naive CD4 + T cell ( Goenka et al., 2011) ( Fig. Instead, Tfh cell differentiation is a multistep, multisignal process that also accommodates a significant amount of heterogeneity. There is no single event that defines Tfh cell differentiation, unlike Th1 cell differentiation for instance, which can be fully induced by interleukin-12 (IL-12) exposure in vitro or in vivo. Tfh cell differentiation is a multi-stage, multi-factorial process. For an oral presentation of the review see supplemental video 1. In addition, a new conceptual model is introduced to explain the relationship between Tfh cell and other CD4 + T cell differentiation programs. This article reviews our understanding of Tfh cell differentiation, molecular biology, and function, and discusses the most recent advances in these areas as well as the complexities of Tfh cell biology. The field of Tfh cell biology has now exploded with activity, examining everything from the biochemistry of transcription factors involved in programming Tfh cell differentiation to the cellular biology of Tfh cell-mediated selection of germinal center B cells, and examining important roles of Tfh cells in biological processes as diverse as vaccine elicited immune responses to chronic autoimmune diseases and even to roles of Tfh cells in protective immunity in human cancers. ![]() While the first evidence of Tfh cells was reported in human lymphoid tissue more than a decade ago, much of the interest in Tfh cells traces its origins to the identification of Bcl6 as an essential transcription factor in CD4 + T cells for Tfh cell differentiation and the development of germinal centers (GCs) ( Johnston et al., 2009 Nurieva et al., 2009 Yu et al., 2009). There has been a great deal of recent activity in the study of T follicular helper (Tfh) cells.
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