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. 2013 Aug 13;110(33):13498-503.
doi: 10.1073/pnas.1307572110. Epub 2013 Jul 29.

Virtual memory CD8 T cells display unique functional properties

June-Yong Lee  1 , Sara E Hamilton, Adovi D Akue, Kristin A Hogquist, Stephen C Jameson
Affiliations

Virtual memory CD8 T cells display unique functional properties

June-Yong Lee et al. Proc Natl Acad Sci U S A. .

Abstract

Previous studies revealed the existence of foreign antigen-specific memory phenotype CD8 T cells in unimmunized mice. Considerable evidence suggests this population, termed "virtual memory" (VM) CD8 T cells, arise via physiological homeostatic mechanisms. However, the antigen-specific function of VM cells is poorly characterized, and hence their potential contribution to immune responses against pathogens is unclear. Here we show that naturally occurring, polyclonal VM cells have unique functional properties, distinct from either naïve or antigen-primed memory CD8 T cells. In striking contrast to conventional memory cells, VM cells showed poor T cell receptor-induced IFN-γ synthesis and preferentially differentiated into central memory phenotype cells after priming. Importantly, VM cells showed efficient control of Listeria monocytogenes infection, indicating memory-like capacity to eliminate certain pathogens. These data suggest naturally arising VM cells display unique functional traits, allowing them to form a bridge between the innate and adaptive phase of a response to pathogens.

Keywords: homeostasis; lymphocyte.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Functional traits of VM, naïve, and TM CD8 T cells. (A) Mean fluorescence intensity (MFI) of T-bet and Eomes on Ova/Kb-specific VM, naïve, and TM Vβ5 CD8 T cells. Data are compiled from at least three experiments and error bars show the mean ± SD. (B) IFN-γ production in VM, naïve, and TM Vβ5 CD8 T cells upon in vitro stimulation with OVA peptide. Data show the frequency of TNF-α+, IFN- γ+ cells within the total responsive (TNF-α+) pool. The response was measure at 2 or 5 h after simulation with titrated OVA peptide doses (10−7 M–10−10 M). Graph shows compiled data from at least four independent experiments and lines show mean ± SD. (C) Analysis of cell cycle status on indicated populations. Data are compiled from at least three experiments and bars show the mean ± SD. Statistical significance is indicated (***P < 0.001; NS, not significant, is used to denote P values >0.05, Student t test).
Fig. 2.
Fig. 2.
VM CD8 T cells outcompete their naïve counterparts during the expansion phase of the primary immune response. (A) At the indicated time points following LM-OVA infection, Ova/Kb tetramer+ cells derived from VM and naïve Vβ5 donors in the spleen and superficial lymph nodes were enumerated. Data are shown as absolute numbers or ratio between VM and naïve derived cells. (B) The frequency of CD69 expressing Ova/Kb-tetramer + or Ova/Kb-tetramer− Vβ5 CD8 T cells was determined 5 h after L. monocytogenes-OVA infection. Data show CD69 expression by paired samples of naïve and VM cells in the same recipients. (C) Number of Ova/Kb-specific VM and naïve Vβ5 CD8 T cells during secondary immune respond against LM-OVA. For all experiments, the data are compiled from three independent experiments except day 22 p.i. (A), which were derived from two independent experiments (six mice total). Line graphs show mean ± SD and statistical significance is indicated (***P < 0.001; *P < 0.05; NS, not significant, is used to denote P values >0.05, Student t test).
Fig. 3.
Fig. 3.
Comparisons of phenotype and peripheral residency between VM and naïve CD8 T cells during primary L. monocytogenes infection. (A and B) Short-lived effector (KLRG1+ CD127lo) and memory precursor (KLRG1− CD127hi) phenotype of responding VM and naïve CD8 T cells, during effector and memory phase following LM-OVA infection. Frequencies of phenotypic subsets were determined on Ova/Kb-tetramer+ donor Vβ5 CD8 T cells at the indicated times postinfection. Line graphs show mean ± SD. (C) Central memory (CD62L+) differentiation of responding VM and naïve donor Vβ5 CD8 T cells. The frequency of CD62L+ cells in cotransfered naïve and VM populations is shown. (D) Ratio between Ova/Kb-tetramer-specific VM and naïve Vβ5 CD8 T cells in indicated tissues and blood at 50–60 d post-LM-OVA infection. (Blood contamination in each tissue was excluded as described in SI Materials and Methods). For all experiments, data were compiled from three independent experiments, except day 22 p.i. (two independent experiments; six mice total). Statistical significance between groups is indicated (***P < 0.001; **P < 0.01; *P < 0.05, whereas NS, not significant, is used to denote P values >0.05, Student t test).
Fig. 4.
Fig. 4.
VM and TM CD8 T cells show similar kinetics in proliferation, but distinct effector differentiation. (A) Graphs show the number of cotransferred Ova/Kb-specific VM and TM Vβ5 CD8 T cells in the spleen and superficial lymph nodes at the indicated times post–L. monocytogenes-OVA infection. (B–D) Phenotypic comparison between responding VM and TM CD8 T cells, gated on OVA/Kb tetramer+ donor cells at the indicated days post–L. monocytogenes-OVA infection. Graphs show compiled data from three independent experiments and lines show mean ± SD. Statistical significance between groups is indicated (***P < 0.001; **P < 0.01; NS, not significant, is used to denote P values >0.05, Student t test).
Fig. 5.
Fig. 5.
VM cells provide potent antigen-specific protective immunity against L. monocytogenes infection. Naïve, VM, and TM Vβ5 CD8 T cells were sorted and ∼2 × 104 Ova/Kb-specific cells were singly transferred into unprimed recipients. Host mice were infected the next day with virulent LM-OVA or wild-type L. monocytogenes (LM-WT). (A) Cfu of indicated L. monocytogenes strains in the spleens and livers of the recipient mice 5 d after infection. (B) Number of Ova/Kb-specific CD8 T cells and (C) frequency of KLRG1+CD127− CD8 T cells in the spleens of recipient mice at day 5 post–LM-OVA infection. Graphs show compiled data from four independent experiments for LM-OVA infection and two independent experiments for L. monocytogenes-WT infection and lines show mean ± SD. Statistical significance between groups is indicated (***P < 0.001; **P < 0.01; *P < 0.05; NS, not significant, is used to denote P values >0.05, Student t test).
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