Tolerance and Exhaustion: Defining Mechanisms of T cell Dysfunction

By A. Schietinger, P. Greenberg. Trends in immunology, 2013

633 citations recorded by the source corpus.

CD8 T cell activation and differentiation is tightly controlled, and dependent on the context in which naïve T cells encounter antigen, can either result in functional memory or T cell dysfunction, including exhaustion, tolerance, anergy, or senescence. With the identification of phenotypic and functional traits shared in different settings of T cell dysfunction, distinctions between such dysfunctional `states' have become blurred. Here, we discuss distinct states of CD8 T cell dysfunction, with emphasis on (i) T cell tolerance to self-antigens (self-tolerance), (ii) T cell exhaustion during chronic infections, and (iii) tumor-induced T cell dysfunction. We highlight recent findings on cellular and molecular characteristics defining these states, cell-intrinsic regulatory mechanisms that induce and maintain them, and strategies that can lead to their reversal.

Subfields: Immunology, Neurology

View Paper: https://www.semanticscholar.org/paper/e971bf3a1187a8615d478c3817320cb3b1dce014

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Citations in the corpus

MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade. (2016, background): “Intratumoral T cells in mice and in human cancer patients typically display a loss of effector function: they might be anergic, nonresponsive, or exhausted, and/or be subject to deletion depending on context (Schietinger and Greenberg, 2014).”
Type 1 diabetes (2002, neutral): “Multiple mechanisms have been associated with T cell tolerance in research settings ( 4 , 5 ), but this knowledge has not yet led to long-term therapeutic benefit in T1D ( 1 ).”
Immunity, inflammation, and cancer: an eternal fight between good and evil. (2015, positive): “During persistent infections, chronic inflammation, and tumor development, antigen-specific CD8+ T cells often fail to form effector or memory cells (24, 123) and instead undergo exhaustion, as first described during viral infection (124).”
A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small cell lung cancer treated with PD-1 blockade (2018, neutral): “5 (2D1), -CD56 PE (CMSSB), - CD3 APC-eFluor780 (SK7), -Lag-3 FITC (3DS223H), -TIGIT PE (MBSA43), -2B4 FITC (eBioDM244), -CD137 FITC (4B4), -IL-2 PE (MQ1-17H12), -TNF-α APC (MAb11), - CD26 FITC (2A6), -CXCR5 Biotin (MU5UBEE), -ICOS FITC (ISA-3), -CD38 APC (HIT2), -Eomes eFluor660 (WD1928), -T-bet PE ”
The Principles of Engineering Immune Cells to Treat Cancer (2017, background): “Increasing evidence indicates that tumor-specific T cells in many patients are in various states of exhaustion (Lee et al., 1999; Schietinger and Greenberg, 2014).”
CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. (2019, background): “NFAT is a family of transcription factors with well-established roles in T cell activation (261, 262), T cell anergy (263), and T cell exhaustion (7, 9, 122).”
Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis (2016, positive): “See also Figure S3 and Table S1; for (A) and (C), FDR q value % 0.05. choriomeningitis virus (LCMV) clone 13 infection in mice (Wherry et al., 2007) or human immunodeficiency virus (HIV) infection in humans (Quigley et al., 2010; Schietinger and Greenberg, 2014).”