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Key Publications

Submitted and Published Papers

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Spatial microniches of IL-2 combine with IL-10 to drive lung migratory TH2 cells in response to inhaled allergen

October 11th, 2024, Nature Immunology

The mechanisms that guide T helper 2 (TH2) cell differentiation in barrier tissues are unclear. Here we describe the molecular pathways driving allergen-specific TH2 cells using temporal, spatial and single-cell transcriptomic tracking of house dust mite-specific T cells in mice. Differentiation and migration of lung allergen-specific TH2 cells requires early expression of the transcriptional repressor Blimp-1. Loss of Blimp-1 during priming in the lymph node ablated the formation of TH2 cells in the lung, indicating early Blimp-1 promotes TH2 cells with migratory capability. IL-2/STAT5 signals and autocrine/paracrine IL-10 from house dust mite-specific T cells were essential for Blimp-1 and subsequent GATA3 upregulation through repression of Bcl6 and Bach2. Spatial microniches of IL-2 in the lymph node supported the earliest Blimp-1+TH2 cells, demonstrating lymph node localization is a driver of TH2 initiation. Our findings identify an early requirement for IL-2-mediated spatial microniches that integrate with allergen-driven IL-10 from responding T cells to drive allergic asthma.

Review: Systems immunology approaches to study T cells in health and disease

October 9th, 2024, npj systems biology and applications 

T cells are dynamically regulated immune cells that are implicated in a variety of diseases ranging from infection, cancer and autoimmunity. Recent advancements in sequencing methods have provided valuable insights in the transcriptional and epigenetic regulation of T cells in various disease settings. In this review, we identify the key sequencing-based methods that have been applied to understand the transcriptomic and epigenomic regulation of T cells in diseases.

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Regulation and Immunotherapeutic Targeting of the Epigenome in Exhausted CD8 T Cell Responses

April 1, 2023

Exhaustion is a state of CD8 T cell differentiation that occurs in settings of chronic Ag such as tumors, chronic viral infection, and autoimmunity. Cellular differentiation is driven by a series of environmental signals that promote epigenetic landscapes that set transcriptomes needed for function. For CD8 T cells, the epigenome that underlies exhaustion is distinct from effector and memory cell differentiation, suggesting that signals early on set in motion a process where the epigenome is modified to promote a trajectory toward a dysfunctional state. Although we know many signals that promote exhaustion, putting this in the context of the epigenetic changes that occur during differentiation has been less clear. In this review, we aim to summarize the epigenetic changes associated with exhaustion in the context of signals that promote it, highlighting immunotherapeutic studies that support these observations or areas for future therapeutic opportunities.

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Tumor microenvironmental signals reshape chromatin landscapes to limit the functional potential of exhausted T cells

August 5, 2022; Science Immunology

B. Rhodes Ford*, Paolo D.A. Vignali*, Natalie L. Rittenhouse*, Nicole E. Scharping*, Ronal Peralta, Konstatinos Lontos,  Andrew T. Frisch, Greg M. Delgoffe*, Amanda C. Poholek*

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Tissue-Specific Contributions to Control of T Cell Immunity

June 8, 2021; ImmunoHorizons

Amanda C. Poholek

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Blimp-1 is Essential for Allergen-induced Asthma and Th2 Cell Development in the Lung

May 12, 2020; Journal of Experimental Medicine

Kun He*, Angela Hettinga*, Sagar L. Kale, Sanmei Hu, Markus M. Xie, Alexander L. Dent, Anuradha Ray, Amanda C. Poholek

Additional Publications:

Scharping NE, Rivadeneira DB, Menk AV, Vignali PDA, Ford BR, Rittenhouse NL, Peralta R, Wang Y, Wang Y, DePeaux K, Poholek AC, Delgoffe GM. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat Immunol. 2021 Feb;22(2):205-215. doi: 10.1038/s41590-020-00834-9. Epub 2021 Jan 4.

Poholek AC, Jankovic D, Villarino AV, Petermann F, Hettinga A, Shouval DS, Snapper SB, Kaech SM, Brooks SR, Vahedi G, Sher A, Kanno Y, O'Shea JJ. IL-10 induces a STAT3-dependent autoregulatory loop in TH2 cells that promotes Blimp-1 restriction of cell expansion via antagonism of STAT5 target genes. Sci Immunol. 2016 Oct;1(5):eaaf8612. doi: 10.1126/sciimmunol.aaf8612. Epub 2016 Nov 11.

Poholek AC, Hansen K, Hernandez SG, Eto D, Chandele A, Weinstein JS, Dong X, Odegard JM, Kaech SM, Dent AL, Crotty S, Craft J. In vivo regulation of Bcl6 and T follicular helper cell development. J Immunol. 2010 Jul 1;185(1):313-26. doi: 10.4049/jimmunol.0904023. Epub 2010 Jun 2. PMID: 20519643; PMCID: PMC2891136.

Johnston RJ, Poholek AC, DiToro D, Yusuf I, Eto D, Barnett B, Dent AL, Craft J, Crotty S. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science. 2009 Aug 21;325(5943):1006-10. doi: 10.1126/science.1175870. Epub 2009 Jul 16. PMID: 19608860; PMCID: PMC2766560.

Vahedi G, C Poholek A, Hand TW, Laurence A, Kanno Y, O'Shea JJ, Hirahara K. Helper T-cell identity and evolution of differential transcriptomes and epigenomes. Immunol Rev. 2013 Mar;252(1):24-40. doi: 10.1111/imr.12037. PMID: 23405893; PMCID: PMC3577092.

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