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Link to original content: https://pubmed.ncbi.nlm.nih.gov/22623779
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. 2012 Aug;86(15):8161-70.
doi: 10.1128/JVI.00889-12. Epub 2012 May 23.

Progressive loss of memory T cell potential and commitment to exhaustion during chronic viral infection

Jill M Angelosanto  1 , Shawn D Blackburn, Alison Crawford, E John Wherry
Affiliations

Progressive loss of memory T cell potential and commitment to exhaustion during chronic viral infection

Jill M Angelosanto et al. J Virol. 2012 Aug.

Abstract

T cell exhaustion and loss of memory potential occur during many chronic viral infections and cancer. We investigated when during chronic viral infection virus-specific CD8 T cells lose the potential to form memory. Virus-specific CD8 T cells from established chronic infection were unable to become memory CD8 T cells if removed from infection. However, at earlier stages of chronic infection, these virus-specific CD8 T cells retained the potential to partially or fully revert to a memory differentiation program after transfer to infection-free mice. Conversely, effector CD8 T cells primed during acute infection were not protected from exhaustion if transferred to a chronic infection. We also tested whether memory and exhausted CD8 T cells arose from different subpopulations of effector CD8 T cells and found that only the KLRG1(lo) memory precursor subset gave rise to exhausted CD8 T cells. Together, these studies demonstrate that CD8 T cell exhaustion is a progressive developmental process. Early during chronic infection, the fate of virus-specific CD8 T cells remains plastic, while later, exhausted CD8 T cells become fixed in their differentiation state. Moreover, exhausted CD8 T cells arise from the memory precursor and not the terminally differentiated subset of effector CD8 T cells. These studies have implications for our understanding of senescence versus exhaustion and for therapeutic interventions during chronic infection.

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Figures

Fig 1
Fig 1
Virus-specific CD8 T cells at day 30 after LCMV clone 13 infection do not persist if adoptively transferred to infection-free recipients. (A) Experimental design. Ly5.1+ CD8 T cells were purified from day 30 LCMV clone 13-infected mice and adoptively transferred to day 30 LCMV Arm-immune or day 30 LCMV clone 13-infected recipient mice. Approximately 2 × 105 DbGP33+ CD8 T cells were adoptively transferred to each recipient mouse. Donor virus-specific CD8 T cells were examined on days 2 and 60 p.t. (B) Gating strategy used to identify donor CD8 T cell population. Representative examples of the day 30 clone 13 → Arm and day 30 clone 13 → clone 13 recipient mice on both day 2 p.t. and day 60 p.t. (C) Absolute numbers of DbGP33+ CD8 T cells in the spleens of recipient mice on days 2 and 60 p.t. normalized to the number of cells on day 2 p.t. Each symbol represents one mouse, with red squares signifying antigen-specific CD8 T cells transferred to clone 13-infected recipient mice and blue circles representing cells transferred to day 30 Arm-infected recipient mice. ns, not significant; **, P < 0.01.
Fig 2
Fig 2
CD8 T cells from day 15 clone 13-infected mice persisted but formed memory poorly in infection-free recipients. (A) Experimental design. Ly5.2+ CD8 T cells were purified from day 15 LCMV clone 13-infected mice and adoptively transferred to day 15 Arm- or day 15 clone 13-infected recipient mice. Approximately 1 × 105 or 1.5 × 105 donor DbGP33+ CD8 T cells were adoptively transferred to each recipient mouse, with equal numbers of adoptively transferred cells transferred to all donor mice for each individual experiment. Donor virus-specific CD8 T cells were examined on days 5, 15, 30, and 60 p.t. in recipient mouse spleens. (B) Representative fluorescence-activated cell sorter plots of CD44hi DbGP33+ day 15 clone 13 → Arm-infected and day 15 clone 13 → clone 13-infected recipient mice on day 60 p.t. The cells are gated on live CD8+ Ly5.2+ T cells. (C) Mean fluorescence of CD127 and PD-1. The gray histogram in each plot is gated on CD8+ CD44lo naïve T cells. (D) Frequency of PD-1hi and CD127+ CD8+ DbGP33+ T cells on day 60 p.t. (E) Mean fluorescence of CD127 and PD-1 on days 5, 15, and 30 p.t. (F) Percentage of IFN-γ, IL-2, TNF, and IFN-γ plus TNF produced by CD8 T cells following restimulation ex vivo with the GP33 peptide on day 30 p.t. Light blue, endogenous (Endo) Arm response; dark blue, clone 13 → Arm transfer; red, clone 13 → clone 13 transfer; pink, endogenous clone 13 response.
Fig 3
Fig 3
Virus-specific CD8 T cells isolated from LCMV clone 13-infected donor mice on day 8 p.i. can form memory in infection-free recipient mice. (A) Experimental design. Ly5.2+ CD8 T cells were purified from day 8 clone 13-infected mice and adoptively transferred to day 8 Arm- or day 8 clone 13-infected recipient mice. In each experiment, the same number of CD8 T cells was transferred to each recipient mouse, with between 2 × 105 and 3 × 105 donor DbGP33+ CD8 T cells transferred to each recipient per experiment. Donor virus-specific CD8 T cells were examined on days 5, 15, 30, and 60 p.t. in recipient mouse spleens. (B) Representative fluorescence-activated cell sorter plots of CD44hi DbGP33+ day 8 clone 13 → Arm-infected and day 8 clone 13 → clone 13-infected recipient mice on day 30 p.t. The cells are gated on live CD8+ Ly5.2+ T cells. (C) Mean fluorescence of CD127 and PD-1. The gray histogram in each plot is gated on CD8+ CD44lo naïve T cells. (D) Frequency of PD-1hi and CD127+ CD8+ DbGP33+ T cells on day 60 p.t. (E) Mean fluorescence of CD127 and PD-1 on days 5, 15, and 30 p.t. Light blue, endogenous Arm response; dark blue, clone 13 → Arm transfer; red, clone 13 → clone 13 transfer; pink, endogenous clone 13 response.
Fig 4
Fig 4
Optimal priming does not prevent exhaustion of effector CD8 T cells transferred to a chronic infection. (A) Experimental design. Ly5.1+ CD8 T cells were purified from either day 8 or day 15 Arm-infected mice and adoptively transferred (day 8, ∼5 × 105 DbGP33+ CD8 T cells/recipient; day 15, ∼1 × 105 DbGP33+ CD8 T cells/recipient) to infection-matched clone 13- or Arm-infected recipient mice. Donor virus-specific CD8 T cells were examined on days 5, 15, 30, and 60 p.t. in recipient spleens. (B to D) Day 8 Arm → clone 13. (B) Percentage of Ly5.1+ DbGP33+ CD8 T cells expressing CD127 or high levels of PD-1 in the blood; (C) mean fluorescence of IFN-γ, IL-2, and TNF expressed by CD8 T cells restimulated ex vivo with the GP33 peptide on day 60 p.t.; (D) polyfunctionality of day 8 Arm → Arm and day 8 Arm → clone 13. Colors represent the number of cytokines (1 to 5) coproduced per cell. (E to G) Day 15 Arm → clone 13. (E) Percentage of Ly5.1+ DbGP33+ CD8 T cells expressing CD127 or high levels of PD-1 in the blood; (F) mean fluorescence of IFN-γ, IL-2, and TNF expressed by CD8 T cells restimulated ex vivo with the GP33 peptide on day 60 p.t.; (G) polyfunctionality of day 15 Arm → Arm and day 15 Arm → clone 13 displayed as in panel D. MFI, mean fluorescence intensity; MIP1α, macrophage inflammatory protein-1α.
Fig 5
Fig 5
Exhausted virus-specific CD8 T cells arise from the KLRG1lo memory precursor population of effector cells. (A) KLRG1 expression on day 8 p.i. with Arm and clone 13. (B) Experimental design. Ly5.2+ CD44hi DbGP33+ CD8 T cells from either day 8 Arm- or day 8 clone 13-infected donor mice were sorted into KLRG1hi and KLRG1lo populations. Equal numbers of virus-specific KLRG1hi- or KLRG1lo-sorted populations were adoptively transferred into day 8 clone 13-infected recipient mice and analyzed at 1 to 2 months p.t. Approximately 2.9 × 105 KLRG1hi or KLRG1lo DbGP33+ CD8 T cells were transferred to each recipient in the Arm → clone 13 experiment, and 1.4 × 105 cells were transferred in the clone 13 → clone 13 control experiment. (C to E) KLRG1hi and KLRG1lo CD8+ DbGP33+ T cells from day 8 Arm-infected mice adoptively transferred into day 8 clone 13-infected recipients. (C) Representative plots of the endogenous (Ly5.2-negative [Ly5.2−]) and KLRG1-sorted (Ly5.2+) donor populations at 2 months p.t.; (D) absolute number of each transferred population on day 60 p.t.; (E) representative plots from KLRG1lo recipient mice on day 60 p.t. The mean fluorescence of CD127 and PD-1 is shown in red or pink, with CD8+ CD44lo naïve T cells shown in the gray histograms. (F and G) KLRG1hi or KLRG1lo CD8+ DbGP33+ T cells from day 8 clone 13-infected mice adoptively transferred into day 8 clone 13-infected recipients. (F) Representative plots of the endogenous (Ly5.2−) and KLRG1-sorted (Ly5.2+) donor populations at 2 months p.t.; (G) absolute number of each transferred population on day 60 p.t. (H) Representative plots from KLRG1lo recipient mice on day 60 p.t. The mean fluorescence of CD127 and PD-1 is shown in red or pink, with CD8+ CD44lo naïve T cells shown in the gray histograms.
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