TCF1 Is Required for the T Follicular Helper Cell Response to Viral Infection

Wu, Tuoqi; Shin, Hyun Mu; Moseman, E. Ashley; Ji, Yun; Huang, Bruce; Harly, Christelle; Sen, Jyoti Misra; Berg, Leslie J.; Gattinoni, Luca; McGavern, Dorian B.; Schwartzberg, Pamela L.

doi:10.1016/j.celrep.2015.08.049

Cited by 139 publications

(177 citation statements)

References 53 publications

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“…However, the LCMV-specific CD8 + T cells appear by day 8 post infection and also express other Tfh-associated proteins including ICOS, Bcl6, and PD-1 59,61,62 . The development of CXCR5+ CD8 + T cells in clone 13 infection is dependent on the transcription factor Tcf-1, consistent with its role in CD4 + Tfh differentiation (Box 1) 32–34,59,61 . The functional role of CXCR5+ CD8 + T cells is incompletely understood, but recent data in LCMV suggest that CXCR5+ LCMV-specific CD8 + T cells control viremia better than their CXCR5-negative counterparts 59,62 .…”

Section: Cd4+ T Responses In Mouse Models Of Chronic Infectionsupporting

confidence: 52%

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CD4+ T Cell Differentiation in Chronic Viral Infections: The Tfh Perspective

Vella

Herati

Wherry

2017

Trends in Molecular Medicine

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CD4+ T cells play a critical role in the response to chronic viral infections during the acute phase and in the partial containment of infections once chronic infection is established. As infection persists, the virus-specific CD4+ T cell response begins to shift in phenotype. The predominant change described in both mouse and human studies of chronic viral infection is a decrease in detectable Th1 responses. Some Th1 loss is due to decreased proliferative potential and decreased cytokine production in the setting of chronic antigen exposure. However, recent data suggest that Th1 dysfunction is accompanied by a shift in the differentiation pathway of virus-specific CD4+ T cells, with enrichment for cells with a T follicular helper cell (Tfh) phenotype. A Tfh-like program during chronic infection has now been identified in virus-specific CD8+ T cells as well. In this review, we discuss what is known about CD4+ T cell differentiation in chronic viral infections, with a focus on the emergence of the Tfh program and the implications of this shift with respect to Tfh function and the host-pathogen interaction.

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Section: Cd4+ T Responses In Mouse Models Of Chronic Infectionsupporting

confidence: 52%

“…Lef-1, and Tcf-1) and costimulatory molecules (e.g. ICOS) are also important in the initiation of the mouse Tfh program 32–36 . While these processes are critical in early Tfh differentiation, nascent Tfh cells require functional B cell interactions to complete Tfh commitment 37,38 .…”

Section: Viral Infections and The T Cell Responsementioning

confidence: 99%

CD4+ T Cell Differentiation in Chronic Viral Infections: The Tfh Perspective

Vella

Herati

Wherry

2017

Trends in Molecular Medicine

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“…During early stage of viral infection, virus-specific Tfh cells reciprocally express TCF-1 and Blimp-1 (129). The TCF-1 deficiency led to poor differentiation of Tfh cells and their maintenance.…”

Section: Cytokine As Positive and Negative Regulators Of Tfh Differenmentioning

confidence: 99%

Regulators of Tfh Cell Differentiation

2016

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The follicular helper T (Tfh) cells help is critical for activation of B cells, antibody class switching, and germinal center (GC) formation. The Tfh cells are characterized by the expression of CXC chemokine receptor 5 (CXCR5), ICOS, programed death 1 (PD-1), B cell lymphoma 6 (BCL-6), and IL-21. They are involved in clearing infections and are adversely linked with autoimmune diseases and also have a role in viral replication as well as clearance. On the one hand, Tfh cells are generated from naive CD4+ T cells with sequential steps involving cytokine signaling (IL-21, IL-6, IL-12, activin A), migration, and positioning in the GC by CXCR5, surface receptors (ICOS/ICOSL, signaling lymphocyte activation molecule-associated protein/signaling lymphocyte activation molecule) as well as transcription factor (BCL-6, c-Maf, and signal transducer and activator of transcription 3) signaling and repressor miR155. On the other hand, Tfh generation is negatively regulated at specific steps of Tfh generation by specific cytokine (IL-2, IL-7), surface receptor (PD-1, CTLA-4), transcription factors B lymphocyte maturation protein 1, signal transducer and activator of transcription 5, T-bet, KLF-2 signaling, and repressor miR 146a. Interestingly, miR-17–92 and FOXO1 act as a positive as well as a negative regulator of Tfh differentiation depending on the time of expression and disease specificity. Tfh cells are also generated from the conversion of other effector T cells as exemplified by Th1 cells converting into Tfh during viral infection. The mechanistic details of effector T cells conversion into Tfh are yet to be clear. To manipulate Tfh cells for therapeutic implication and or for effective vaccination strategies, it is important to know positive and negative regulators of Tfh generation. Hence, in this review, we have highlighted and interlinked molecular signaling from cytokines, surface receptors, transcription factors, ubiquitin ligase, and microRNA as positive and negative regulators for Tfh differentiation.

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“…Bcl6 plays a central role in Tfh cell differentiation,115, 137, 138 but other transcription factors that act upstream and downstream of Bcl6 are also required (reviewed in 139). These include lymphoid enhancer‐binding factor 1 (LEF‐1) and T‐cell‐specific transcription factor 1 (TCF‐1), which act upstream of Bcl6 to promote Tfh cell differentiation140, 141, 142; basic leucine zipper transcription factor ATF‐like (Batf), which positively regulates Bcl6 and is important for IL‐4 expression143; interferon regulatory factor 4 (IRF4), which drives differentiation of IL‐12‐stimulated CD4 T cells to Tfh rather than Th1 cells144; achaete‐scute homolog 2 (Ascl2), which induces CXCR5 expression145; c‐Maf, which enhances expression of CXCR5, IL‐21, and IL‐4146; signal transducer and activator of transcription (STAT)s, STAT3 and 4 being particularly important for human Tfh cell differentiation and regulation of IL‐21 expression by human CD4 + T cells121, 147; and forkhead box protein O1 (FOXO1), which can both promote and inhibit Tfh cell differentiation 148. In addition, Tfh cell differentiation is regulated by microRNAs including members of the miRNA‐17‐92 family 149, 150.…”

Section: T Follicular Helper Cells and Their Role In Bnab Inductionmentioning

confidence: 99%

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

Borrow

Moody

2017

Immunological Reviews

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SummaryInduction of broadly neutralizing antibodies (bnAbs) capable of inhibiting infection with diverse variants of human immunodeficiency virus type 1 (HIV‐1) is a key, as‐yet‐unachieved goal of prophylactic HIV‐1 vaccine strategies. However, some HIV‐infected individuals develop bnAbs after approximately 2‐4 years of infection, enabling analysis of features of these antibodies and the immunological environment that enables their induction. Distinct subsets of CD4+ T cells play opposing roles in the regulation of humoral responses: T follicular helper (Tfh) cells support germinal center formation and provide help for affinity maturation and the development of memory B cells and plasma cells, while regulatory CD4+ (Treg) cells including T follicular regulatory (Tfr) cells inhibit the germinal center reaction to limit autoantibody production. BnAbs exhibit high somatic mutation frequencies, long third heavy‐chain complementarity determining regions, and/or autoreactivity, suggesting that bnAb generation is likely to be highly dependent on the activity of CD4+ Tfh cells, and may be constrained by host tolerance controls. This review discusses what is known about the immunological environment during HIV‐1 infection, in particular alterations in CD4+ Tfh, Treg, and Tfr populations and autoantibody generation, and how this is related to bnAb development, and considers the implications for HIV‐1 vaccine design.

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TCF1 Is Required for the T Follicular Helper Cell Response to Viral Infection

Cited by 139 publications

References 53 publications

CD4+ T Cell Differentiation in Chronic Viral Infections: The Tfh Perspective

CD4+ T Cell Differentiation in Chronic Viral Infections: The Tfh Perspective

Regulators of Tfh Cell Differentiation

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

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