Submitted and Published Papers
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.
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*
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.