Blimp-1–mediated CD4 T cell exhaustion causes CD8 T cell dysfunction during chronic toxoplasmosis

Hwang, Sujin; Cobb, Dustin; Bhadra, Rajarshi; Youngblood, Benjamin A.; Khan, Imtiaz Ali

doi:10.1084/jem.20151995

Cited by 75 publications

(93 citation statements)

References 70 publications

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“…In addition, Blimp-1 is a critical regulator of CD4 T cell exhaustion with elevated levels of inhibitory factors being expressed during chronic toxoplasmosis [67]. Therefore, Blimp-1 is highly upregulated in exhausted CD4 + T cells.…”

Section: The Effects Of Blimp-1 On T Cell Functionsmentioning

confidence: 99%

New insights into Blimp-1 in T lymphocytes: a divergent regulator of cell destiny and effector function

Yeh

Chu

et al. 2017

J Biomed Sci

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B lymphocyte-induced maturation protein-1 (Blimp-1) serves as a master regulator of the development and function of antibody-producing B cells. Given that its function in T lymphocytes has been identified within the past decade, we review recent findings with emphasis on its role in coordinated control of gene expression during the development, differentiation, and function of T cells. Expression of Blimp-1 is mainly confined to activated T cells and is essential for the production of interleukin (IL)-10 by a subset of forkhead box (Fox)p3+ regulatory T cells with an effector phenotype. Blimp-1 is also required to induce cell elimination in the thymus and critically modulates peripheral T cell activation and proliferation. In addition, Blimp-1 promotes T helper (Th) 2 lineage commitment and limits Th1, Th17 and follicular helper T cell differentiation. Furthermore, Blimp-1 coordinates with other transcription factors to regulate expression of IL-2, IL-21 and IL-10 in effector T lymphocytes. In CD8+ T cells, Blimp-1 expression is distinct in heterogeneous populations at the stages of clonal expansion, differentiation, contraction and memory formation when they encounter antigens. Moreover, Blimp-1 plays a fundamental role in coordinating cytokine receptor signaling networks and transcriptional programs to regulate diverse aspects of the formation and function of effector and memory CD8+ T cells and their exhaustion. Blimp-1 also functions as a gatekeeper of T cell activation and suppression to prevent or dampen autoimmune disease, antiviral responses and antitumor immunity. In this review, we discuss the emerging roles of Blimp-1 in the complex regulation of gene networks that regulate the destiny and effector function of T cells and provide a Blimp-1-dominated transcriptional framework for T lymphocyte homeostasis.

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Section: The Effects Of Blimp-1 On T Cell Functionsmentioning

confidence: 99%

New insights into Blimp-1 in T lymphocytes: a divergent regulator of cell destiny and effector function

Yeh

Chu

et al. 2017

J Biomed Sci

View full text Add to dashboard Cite

show abstract

“…5). Other factors that have been shown to have important roles in CD8 + T cells during Ag persistence include Blimp-1 [59][60][61], BATF [57,62], FoxO1 [63], FoxO3 [64,65], and HIF family members [66], among others ( Fig. 1).…”

Section: Other Transcription Factors Implicated In T Cell Hyporesponsmentioning

confidence: 99%

Transcriptional and epigenetic regulation of T cell hyporesponsiveness

Pereira

Hogan

Rao

et al. 2017

Journal of Leukocyte Biology

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Naive CD8 T cells differentiate into effector and memory cytolytic T cells (CTLs) during an acute infection. In contrast, in scenarios of persistent antigen stimulation, such as chronic infections and cancer, antigen-specific CTLs show a gradual decrease in effector function, a phenomenon that has been termed CD8 T cell "exhaustion" or "dysfunction." Another hyporesponsive state, termed "anergy", is observed when T cells are activated in the absence of positive costimulatory signals. Among the many negative regulators induced in hyporesponsive T cells are inhibitory cell-surface receptors, such as PD-1, LAG-3, CTLA-4, and TIM-3; "checkpoint blockade" therapies that involve treatment of patients with cancer with blocking antibodies to those receptors show considerable promise in the clinic because the blocking antibodies can mitigate hyporesponsiveness and promote tumor rejection. In this review, we describe recent advances in our molecular understanding of these hyporesponsive states. We review evidence for the involvement of diverse transcription factors, metabolic programs, and chromatin accessibility changes in hyporesponsive T cells, and we discuss how checkpoint blockade therapies affect the molecular program of CD8 T cell exhaustion.

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“…Similar to CD8 + T cells, dysfunctional CD4 + T cells show a loss of the ability to produce cytokines such as IL-2 and TNFα [13] and acquire the expression of co-inhibitory molecules [12, 14]. Prdm1 (transcription factor also known as BLIMP-1) was reported to drive CD4 + T cell dysfunction [12] and several other transcription factors such as Eomes and Helios were shown to be upregulated in dysfunctional CD4 + T cells relative to naïve and memory CD4 + T cells [14]. Overall, several transcription factors associated with CD4 + T cell dysfunction are also implicated in CD8 + T cell dysfunction, suggesting the evolution of shared regulatory pathways to restrict T cell responses.…”

Section: Figurementioning

confidence: 99%

Molecular Dissection of CD8 + T-Cell Dysfunction

Wang

Singer

Anderson

2017

Trends in Immunology

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Chronic viral infections and cancer often lead to the emergence of dysfunctional or “exhausted” CD8+ T cells, and the restoration of their functions is currently the focus of therapeutic interventions. Here, we detail recent advances in the annotation of the gene modules and the epigenetic landscape associated with T cell dysfunction. Together with analysis of single-cell transcriptomes, these findings have enabled a deeper and more precise understanding of the transcriptional mechanisms that induce and maintain the dysfunctional state and highlight the heterogeneity of CD8+ T cell phenotypes present in chronically inflamed tissue. We discuss the relevance of these findings for understanding the transcriptional and spatial regulation of dysfunctional T cells and for the design of therapeutics.

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Blimp-1–mediated CD4 T cell exhaustion causes CD8 T cell dysfunction during chronic toxoplasmosis

Abstract: Khan et al. demonstrate that in chronic toxoplasmosis, CD4 T cell–intrinsic expression of Blimp-1 results in progressive exhaustion, which in turn contributes to CD8 T cell exhaustion and poor pathogen control.

Cited by 75 publications

References 70 publications

New insights into Blimp-1 in T lymphocytes: a divergent regulator of cell destiny and effector function

New insights into Blimp-1 in T lymphocytes: a divergent regulator of cell destiny and effector function

Transcriptional and epigenetic regulation of T cell hyporesponsiveness

Molecular Dissection of CD8 + T-Cell Dysfunction

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