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Production of IL-10 by CD4+ regulatory T cells during the resolution of infection promotes the maturation of memory CD8+ T cells

Abstract

Memory CD8+ T cells are critical for host defense upon reexposure to intracellular pathogens. We found that interleukin 10 (IL-10) derived from CD4+ regulatory T cells (Treg cells) was necessary for the maturation of memory CD8+ T cells following acute infection with lymphocytic choriomeningitis virus (LCMV). Treg cell–derived IL-10 was most important during the resolution phase, calming inflammation and the activation state of dendritic cells. Adoptive transfer of IL-10-sufficient Treg cells during the resolution phase 'restored' the maturation of memory CD8+ T cells in IL-10-deficient mice. Our data indicate that Treg cell–derived IL-10 is needed to insulate CD8+ T cells from inflammatory signals, and reveal that the resolution phase of infection is a critical period that influences the quality and function of developing memory CD8+ T cells.

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Figure 1: IL-10 is required during the resolution phase of infection to allow optimal maturation of memory CD8+ T cells.
Figure 2: IL-10 is important in insulating CD8+ T cells from inflammatory signals following viral infection.
Figure 3: CD4+ Treg cell–derived IL-10 is critical for the maturation of memory CD8+ T cells.
Figure 4: CD4+ Treg cell–derived IL-10 is necessary for the formation of protective memory CD8+ T cells.
Figure 5: Virus-specific CD8+ T cells from mice lacking CD4+ Treg cell–derived IL-10 display a robust inflammatory gene signature.
Figure 6: Enhanced maturation of DCs and inflammation in the absence of Treg cell–derived IL-10.
Figure 7: Transfer of IL-10-competent CD4+ Treg cells during the resolution phase of LCMV infection is sufficient to 'rescue' the defect in the maturation of memory CD8+ T cells in Il10−/− mice.

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Acknowledgements

We thank J.M.M. den Haan (UV University Medical Center, Amsterdam) for mAb ES5-2A5; and all members of the Kaech and Craft laboratories for discussions and critical reading of the manuscript. Supported by the US National Institutes of Health (RO1AI066232 and R01AI074699 to S.M.K.; R01AR40072, P30AR053495 and R21AR063942 to J.C.; T32AI07019 and F31AG07777 to B.J.L.; and T32GM07205 to S.M.G.) and the Howard Hughes Medical Institute (S.M.K., B.J.L., R.A.F. and T.G.).

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B.J.L., J.C., S.M.K. conceived of and designed the experiments, analyzed the data and wrote the manuscript; and B.J.L., W.C., R.A.A., S.M.G., T.G., Y.L., Y.K., S.H.K. and R.A.F. performed the experiments.

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Correspondence to Joe Craft or Susan M Kaech.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 IL-10 is required for optimal maturation of memory CD8+ NP396+ T cells.

(a) Analysis of the virus-specific CD8+ T cell response 60 days post acute LCMV Armstrong infection. The percentages and numbers of GP33+ T cells along with the (b) representative plots and analysis of the NP396+ T cell response in the spleen of wild type and Il10–/– mice are shown. Percentages and numbers of NP396+ T cells, along with the percentages of CD127+KLRG1-, CD127-KLRG1+, and CD62L+KLRG1- cells in the NP396+ T cell population are shown. (c) Mice were infected with acute LCMV and treated with αIL-10 between days 0-30, 0-8, 8-30, 15-30 or mock injected with PBS. Mice were sacrificed at day 30 and the percentage and numbers of GP33+ T cells determined. Statistical analyses were performed using the unpaired two-tailed Student’s t-test. (*, p < 0.01; **, p < 0.001). Data are from one experiment representative of 5 experiments (a, b) or 3 experiments (c) with at least 4 mice per group carried out 45-60 days (a, b) or 30 days (c) following LCMV Armstrong infection (mean and s.e.m).

Supplementary Figure 2 IL-10 is required in a CD8+ T cell–extrinsic and CD8+ T cell–intrinsic manner to allow the maturation and survival of memory CD8+ T cells.

50,000 Il10raf/f or Il10raf/fCd4-Cre P14 GP33+ cells were transferred into congenically-mismatched mice one day prior to infection with acute LCMV infection. Analysis of the P14 GP33+ T cell response was carried out 30 days p.i. (a) Representative plots and analysis of the P14 GP33+ T cell response. Percentages and numbers of P14 GP33+ T cells, along with the percentages of CD127+KLRG1-, CD127-KLRG1+, and CD62L+KLRG1- cells in the P14 GP33+ T cell population are shown. (b) Representative histograms of GzmB and Tcf1 expression in Il10raf/f (black) or Il10raf/fCd4-Cre (gray filled) P14 GP33+ cells. Statistical analyses were performed using the unpaired two-tailed Student’s t-test. (*, p < 0.05; **, p < 0.01). Data are from one experiment representative of 2 experiments with 4 mice per group carried out 30 days following LCMV Armstrong infection (mean and s.e.m).

Supplementary Figure 3 CD4+ Treg cells continue to produce IL-10 during the resolution phase of infection.

(a) Analysis of the GP33+ T cell response 60 days post acute LCMV infection in Il10f/f, Il10f/fCd4-Cre, Il10f/fLyz2-Cre, and Il10f/fCd11c-Cre mice. Percentages and numbers of GP33+ T cells were determined. (b) Analysis of IL-10 production by T cells following acute LCMV infection in IL-10 reporter (10BiT Thy1.1 mice). Percentages and numbers of IL-10-Thy1.1 reporter-positive cells at multiple time points post LCMV infection are shown. (c) Intravenously (i.v.) administered anti-CD4 antibody was used to distinguish circulating (red pulp localized) versus resident (white pulp localized) CD4+ T cells. (d) Analysis of the GP33+ T cell response 60 days post acute LCMV Armstrong infection. Percentages and numbers of GP33+ T cells in Il10f/f and Il10f/f Foxp3-Cre mice are shown. Data are from one experiment representative of 3 experiments (a, b, c, d) with 3-6 mice per group carried out 45-60 days (a, d), or 0, 8, and 15 days (b, c) following LCMV Armstrong infection (mean and s.e.m).

Supplementary Figure 4 Validation of RNA-seq results.

(a) Expression of Zeb2, Ccr7, Cx3cr1, and Pim1 was determined by qPCR analysis of cDNA isolated from pooled GP33+ and NP396+ CD8+ T cells at 15 days post acute LCMV infection from Il10f/f and Il10f/f Foxp3-Cre mice. Expression of TCF-1 and GzmB in GP33+ in T cells at 15 days post acute LCMV infection from Il10f/f and Il10f/f Foxp3-Cre mice was determined by flow cytometric analysis. (b) Representative plots of the GP33+ T cell response in Il10f/f and Il10f/f Foxp3Cre mice at day 15 post LCMV infection. Data are from one experiment representative of 3 experiments with 3-5 mice per group carried out 15 days following LCMV Armstrong infection (mean and s.e.m).

Supplementary Figure 5 Heat map of differentially expressed genes based on RNA-seq results.

Genes with a p-adjusted value < 0.2 (Benjami-Hochberg) and the corresponding log2 fold-change in mRNA isolated from pooled GP33+ and NP396+ CD8+ T cells at 15 days post acute LCMV infection from Il10f/f and Il10f/f Foxp3-Cre mice.

Supplementary Figure 6 Virus-specific CD8+ T cells from mice lacking CD4+ Treg cell–derived IL-10 display a robust inflammatory and effector gene signature.

mRNA was isolated from pooled GP33+ and NP396+ CD8+ T cells at 15 days post acute LCMV infection from Il10f/f and Il10f/f Foxp3-Cre mice and compared by RNA-seq. (a) Gene set plots showing individual log2 fold-changes of with corresponding standard error based on published effector vs memory gene set. Gene Set Enrichment Analysis (GSEA) was performed using gene sets from the Broad MSigDB collection; select significantly enriched gene sets (FDR < 1e-5) are shown with their running Enrichment Score (ES) (line), where members of the gene set appear in the ranked list of genes (barcode), and the signal to noise ranking metric (bar). A positive ES signifies enrichment in the Il10f/f Foxp3-Cre sample relative to the WT condition of a given gene set; i.e., more highly expressed. (b) GSEA results of CpG (c) and poly:IC stimulated genes (bottom) were visualized. (d) Normalized enrichment scores for Gene Set Enrichment Analysis. Normalized enrichment scores (NES) was calculated for select significantly enriched gene sets (FDR < 1e-5). Gene set name, figure GSEA plots shown in, and NES are shown in table.

Supplementary Figure 7 Transfer of IL-10-competent CD4+ Treg cells during the resolution phase of LCMV infection is sufficient to ‘rescue’ the maturation defect of memory CD8+ T cells in Il10–/– mice.

Analysis of the GP33+ T cell response 60 days p.i. in Foxp3GFP-DTR mice treated with diphtheria toxin at day -1, day 8, or day 15 p.i. or mock injected with PBS. (a) Percentage and numbers of GP33+ T cells are shown. Representative of 3 independent experiments with 3-6 mice per group carried out 45-60 days following LCMV Armstrong infection. (b) Analysis of the GP33+ T cell response 60 days post acute LCMV Armstrong infection in Il10–/– mice and Il10–/– mice that were administered 3x105 Foxp3+ CD4+ T cells isolated from coinfected Foxp3GFP-DTR mice at day 8 p.i. Percentage and numbers of GP33+ T cells are shown. Representative of 2 independent experiments with 3-7 mice per group carried out 60 days following LCMV Armstrong infection. Data are from one experiment representative of 3 experiments (a) or 2 experiments (b) with 3-7 mice per group carried out 45-60 days following LCMV Armstrong infection (mean and s.e.m).

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Laidlaw, B., Cui, W., Amezquita, R. et al. Production of IL-10 by CD4+ regulatory T cells during the resolution of infection promotes the maturation of memory CD8+ T cells. Nat Immunol 16, 871–879 (2015). https://doi.org/10.1038/ni.3224

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