Progenitor and Terminal Subsets of CD8+ T Cells Cooperate to Contain Chronic Viral Infection

By Michael A. Paley, D. Kroy, P. Odorizzi, Jonathan B. Johnnidis, Douglas V. Dolfi, Burton E. Barnett, E. Bikoff, E. Robertson, G. Lauer, S. Reiner and 1 more. Science, 2012

886 citations recorded by the source corpus.

Chronic infections strain the regenerative capacity of antiviral T lymphocyte populations, leading to failure in long-term immunity. The cellular and molecular events controlling this regenerative capacity, however, are unknown. We found that two distinct states of virus-specific CD8+ T cells exist in chronically infected mice and humans. Differential expression of the T-box transcription factors T-bet and Eomesodermin (Eomes) facilitated the cooperative maintenance of the pool of antiviral CD8+ T cells during chronic viral infection. T-bethi cells displayed low intrinsic turnover but proliferated in response to persisting antigen, giving rise to Eomeshi terminal progeny. Genetic elimination of either subset resulted in failure to control chronic infection, which suggests that an imbalance in differentiation and renewal could underlie the collapse of immunity in humans with chronic infections. Chronic viral infections like HIV are kept in check by two functionally distinct types of T lymphocyte. Chronic infections like hepatitis C virus (HCV) or HIV are hard on the immune system. In the face of a constant threat, some immune cells like T lymphocytes become “exhausted”; although present, they can no longer mount responses that are effective enough to eliminate the virus. These responses, however, are still important because in many cases they do keep the virus relatively controlled. The mechanisms underlying the population dynamics of T cell responses during chronic viral infection, however, are not well understood. Paley et al. (p. 1220) now demonstrate that the T-box transcription factors T-bet and Eomesodermin differentially regulate two phenotypically and functionally distinct subsets of antiviral CD8+ T cells in mice. The cooperation of these subsets may be important for antiviral immunity during chronic viral infections in humans.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/62e5e4d88e02c1a79665e8022c9314b74e7bf1cc

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Citations in the corpus

T Cell Dysfunction in Cancer (2018, background): “…cells is further complicated by the fact that many of these transcription factors act in a contextspecific manner, with a different function in exhausted T cells than in non-exhausted effector or memory T cell subsets (Kao et al., 2011; Paley et al., 2012; Quigley et al., 2010; Shin et al., 2009).”
Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade (2016, neutral): “Thus, PD1 blockade preferentially reinvigorates PD1intEomes– TEX that are Tbet + to give rise to PD1highEomes+ TEX (Blackburn Cell 167, 1540–1554, December 1, 2016 1551 et al., 2008; Paley et al., 2012).”
Distinct Immune Cell Populations Define Response to Anti-PD-1 Monotherapy and Anti-PD-1/Anti-CTLA-4 Combined Therapy. (2019, positive): “Others have identified the TBETHighEOMESLow CD8+ T cells as a partially exhausted T cell population that has the potential to be reinvigorated by anti-PD-1 in the context of chronic viral infections (Blackburn et al., 2008; Paley et al., 2012).”
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 ”
Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade (2018, positive): “In our study, tumor bearing DIO mice showed higher expression of Eomes than T-bet, which supports an exhausted CD8+ T cell profile 4,42 .”
Bioenergetic insufficiencies due to metabolic alterations regulated by PD-1 are an early driver of CD8+ T cell exhaustion (2016, background): “Whereas both subsets are required for control of chronic infection, the PD-1Int subset functions as a progenitor pool giving rise to terminally differentiated PD-1Hi cells (Paley et al., 2012).”
Defining T cell states associated with response to checkpoint immunotherapy in melanoma (2018, neutral): “EOMES was highly expressed in DP cells consistent with previous studies (Paley et al., 2012; Wherry et al., 2007); however, differential peak motif gulated in the corresponding cluster relative to the rest of the cells found in the ion (upper) and TCF7 and GZMB expression (lower). in a…”