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IFNγ-induction of TH1-like regulatory T cells controls antiviral responses

Nature Immunology volume 24, pages 841–854 (2023)Cite this article

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Abstract

Regulatory T (Treg) cells are an immunosuppressive population that are required to maintain peripheral tolerance and prevent tissue damage from immunopathology, via anti-inflammatory cytokines, inhibitor receptors and metabolic disruption. Here we show that Treg cells acquire an effector-like state, yet remain stable and functional, when exposed to interferon gamma (IFNγ) during infection with lymphocytic choriomeningitis and influenza A virus. Treg cell-restricted deletion of the IFNγ receptor (encoded by Ifngr1), but not the interleukin 12 (IL12) receptor (encoded by Il12rb2), prevented TH1-like polarization (decreased expression of T-bet, CXC motif chemokine receptor 3 and IFNγ) and promoted TH2-like polarization (increased expression of GATA-3, CCR4 and IL4). TH1-like Treg cells limited CD8+ T cell effector function, proliferation and memory formation during acute and chronic infection. These findings provide fundamental insights into how Treg cells sense inflammatory cues from the environment (such as IFNγ) during viral infection to provide guidance to the effector immune response. This regulatory circuit prevents prolonged immunoinflammatory responses and shapes the quality and quantity of the memory T cell response.

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Fig. 1: Treg cells acquire a TH1-like program during acute and chronic infection.
Fig. 2: Transcriptomic analysis reveals IFNγ-induced TH1 profiles in Treg cells during chronic infection.
Fig. 3: Ifngr1-deficient Treg cells program to a TH2 phenotype during viral infection.
Fig. 4: IL12 does not induce TH1-like nor suppress TH2-like programming during chronic infection.
Fig. 5: TH1-like Treg cells limit T cell effector function during chronic infection.
Fig. 6: IFNγ from CD8+ T cells but not Treg cells contributes to TH1 polarization of Treg cells during chronic infection.
Fig. 7: TH1-like Treg cells limit CD8+ T memory formation and response to vaccination during acute and chronic infection.

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Data availability

The RNA sequencing data that support the findings of this study have been deposited in the GEO under the accession code GSE223210. All other data are present in the article and Supplementary files or from the corresponding author upon reasonable request. Source data files are present. Source data are provided with this paper.

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Acknowledgements

We thank everyone in the Vignali Lab (Vignali-lab.com; @Vignali_Lab) for all their constructive comments and advice. We thank R. Ahmed (Emory University) for providing parental LCMV viral stocks and protocols, S. Kaech (Yale University) for providing LM-GP33 stocks and protocols, L. D’Cruz and A. Piccirillo (University of Pittsburgh) for providing LM-OVA stocks and protocols, S. Canna, E. Rapp, P. Tsoukas and H. Nieves-Rosado (University of Pittsburgh) for growing up LCMV viral stocks, C. Workman for intravenous injections, E. Brunazzi for maintenance of mouse colonies, R. Dadey for helping with flow cytometry staining on LCMV-infected samples, C. Liu for aiding in flow cytometry panel design, C. Cardello for conducting libraries for scRNA-seq, H. Yano for constructing SPICE plots, D. Normolle for calculating statistics for the weight loss curves, L. Andrews for weighing mice and conducting intravenous injections, L. Rigatti for scoring livers, the University of Pittsburgh Biospecimen Core for histology, the University of Pittsburgh Innovative Technologies Development Core for developing new mouse strains, the University of Pittsburgh Center for Research Computing (HTC cluster) for next-generation sequencing and the University of Pittsburgh Flow Core for FACS and flow cytometry. This work was supported by the National Institutes of Health (F32 CA247004-01 and T32 CA082084 to A.M.G.D.; P01 AI108545, R35 CA263850 and R01 CA203689 to D.A.A.V.; R01 DK130897, R21 CA259636, P30 DK120531 and P30 CA047904 to M.M.; R01 HL107380 to J.F.A.; and R01 CA206517 and R01 AI138504 to L.P.K.). This work benefited from a SPECIAL ORDER BD LSR FORTESSA (funded by NIH 1S10 OD011925-01) used in the UPSOM Unified Flow Core and the University of Pittsburgh Center for Research Computing (funded by NIH S10OD028483).

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Authors and Affiliations

  1. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Angela M. Gocher-Demske, Jian Cui, Andrea L. Szymczak-Workman, Kate M. Vignali, Julianna N. Latini, Gwen P. Pieklo, Jesse C. Kimball, Lyndsay Avery, Lee Hedden, Marlies Meisel, Lawrence P. Kane, Creg J. Workman & Dario A. A. Vignali

  2. Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Angela M. Gocher-Demske, Jian Cui, Kate M. Vignali, Julianna N. Latini, Gwen P. Pieklo, Jesse C. Kimball, Creg J. Workman & Dario A. A. Vignali

  3. Program in Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA

    Lyndsay Avery, Brydie R. Huckestein & John F. Alcorn

  4. Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA

    Ellyse M. Cipolla

  5. Program in Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Ellyse M. Cipolla & Brydie R. Huckestein

  6. Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA

    Marlies Meisel, Lawrence P. Kane & Dario A. A. Vignali

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  1. Angela M. Gocher-Demske
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Contributions

D.A.A.V. conceived, directed and obtained funding for the project. A.M.G.D., C.J.W. and D.A.A.V. conceptualized, designed and analyzed the experiments and wrote the manuscript. A.M.G.D. performed the majority of the experiments. J.C. performed the analysis of the scRNA-seq dataset. A.L.S.W., K.M.V. and C.J.W. generated new mouse strains. J.N.L., G.P.P and J.C.K. helped with processing the tissues before flow cytometry and FACS. J.N.L. helped with LM-GP33 experiments and plaque assays. G.P.P. validated mouse strains, performed qPCRs and isolated splenic T cells. J.C.K. performed qPCRs and isolated splenic T cells. L.A.A. and L.P.K. helped with the LCMV and LM-GP33 model and L.A.A. conducted some Arm. experiments. E.M.S. and B.R.H. infected mice with IAV and helped in necroscopy. L.H. and M.M. performed the ALT and AST activity assay. J.F.A. and C.J.W. contributed to experimental design and interpretation of the data. J.F.A. scored infected lungs. All authors provided feedback and approved the manuscript.

Corresponding author

Correspondence to Dario A. A. Vignali.

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Competing interests

D.A.A.V. is a cofounder and stockholder for Novasenta, Potenza, Tizona and Trishula, is a stockholder for Oncorus, Werewolf and Apeximmune, holds patents licensed and royalties in BMS and Novasenta, serves on a scientific advisory board for Tizona, Werewolf, F-Star, Bicara, Apeximmune and T7/Imreg Bio and is a consultant for BMS, Incyte, G1 Therapeutics, Inzen Therapeutics, Regeneron and Avidity Partners. All the other authors declare no competing interests.

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Extended data

Extended Data Fig. 1 IFNγ and T-bet expression in Treg cells during acute and chronic infection.

a, Gating strategy for all flow cytometric experiments. b-f, Foxp3Cre-YFP mice remained uninfected (n = 5) or were infected (n = 6) with Arm. or Cl. 13. b, c, Expression of Ifng (b) and Tbx21 (c) mRNA by purified splenic Treg cells were determined by qPCR after ex vivo stimulation with anti-CD3/anti-CD28 (Arm.) or PMA and Ionomycin (Cl. 13). c, Linear regression of Tbx21 and Ifng co-expression. d, Foxp3Cre-YFP mice (n = 14) were infected with Arm. and stimulated ex vivo with anti-CD3 and expression of T-bet and IFNγ was measured by flow cytometry. Linear regression of T-bet and IFNγ co-expression. e, f, Foxp3Cre-YFP mice remained uninfected or were infected with Arm. or Cl. 13. Expression of Ifng (e) (n = 15, 5 independent experiments, Uninfected; n = 12, Arm.; n = 17 Cl. 13) and Tbx21 (f) (n = 16, 5 independent experiments, Uninfected; n = 12, Arm.; n = 14, Cl. 13) mRNA by sorted splenic CD4+ Tconv cells and Treg cells, without stimulation, were determined by qPCR. b-f, Data are presented as mean values and represent biologically independent mice and (b-d and as indicated) or 3 (e, f) or 5 (as indicated) independent experiments. Statistical significance was determined by multiple unpaired Student’s t-test relative to Uninfected (b, c), or by simple linear regression (d) or by a two-way ANOVA with multiple comparisons and multiple unpaired t-tests relative to CD4+ Tconv cells (e, f) (P values indicated when significant); NS, not significant.

Source data

Extended Data Fig. 2 TH1 signatures in Treg cells and CD4+ Tconv cells during acute and chronic infection.

a, Diagram of Il12rb2.Thy1.1 L/LhNGR targeted mouse. b, c, Il12rb2.Thy1.1 L/LhNGR mice (n = 11) were infected with Arm. and splenic Thy1.1– and Thy1.1+ CD4+ Tconv. cells purified and expression of Il12rb2 by Thy1.1– and Thy1.1+ CD4+ Tconv. cells was determined by qPCR (b). Thy1.1– and Thy1.1+ CD4+ Tconv. cells were serum starved and treated with PBS or IL-12, and induction of pSTAT4 was measured by flow cytometry (c). d, e, Foxp3Cre-YFP mice (n = 16, 5 independent experiments, Uninfected; n = 12, Arm.; n = 14, Cl. 13) remained uninfected or were infected with Arm. or Cl. 13, expression of Il12rb2 mRNA (d) and Ifngr1 mRNA (e) by sorted splenic CD4+ Tconv cells and Treg cells, without stimulation, were measured by qPCR. f-i, Expression of IFNGR1 (f) (n = 7, 2 independent experiments, Uninfected; n = 9, 2 independent experiments, Arm.; n = 15, Cl. 13), T-bet (g) (n = 7, Uninfected; n = 11, Arm.; n = 8, Cl. 13), CXCR3 (h) (n = 11, Uninfected; n = 9, 2 independent experiments, Arm.; n = 15, Cl. 13), T-bet (n = 7, 2 independent experiments, Uninfected; n = 11, 2 independent experiments, Arm.; n = 16, Cl. 13), GATA-3 (n = 6, 2 independent experiments, Uninfected; n = 9, 2 independent experiments, Arm.; n = 17, Cl. 13), and RORγt (n = 3, 2 independent experiments, Uninfected; n = 11, 2 independent experiments, Arm.; n = 8, 2 independent experiments, Cl. 13), (i) by splenic CD4+ Tconv cells and Treg cells were determined flow cytometry. b-i, Data are presented as mean values and represent biologically independent mice and 2 (g, and as indicated) or 3 (b-f, h, i) or 5 (as indicated) independent experiments. Statistical significance was determined by an unpaired two-tailed Student’s t-test relative to Thy1.1– (b) or CD4+ Tconv cells (f-h), or by a two-way AVOVA with multiple comparisons (c), or by a two-way ANOVA with multiple comparisons (d-e) and multiple unpaired t-tests relative to CD4+ Tconv cells (d, e, i) (P values indicated when significant); NS, not significant.

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Extended Data Fig. 3 Transcriptomic analysis of Ifngr1-deficient Treg cells verses control, during chronic infection.

a, Expression of the deleted region of Ifngr1, normalized to the intact region of Ifngr1, from uninfected Ifngr1L/LFoxp3Cre-YFP (n = 5) compared to Foxp3Cre-YFP mice (n = 6). Thy1.2– cells, CD8+ T cells, CD4+ Tconv cells and Treg cells were sorted, gDNA was isolated and qPCR was performed. b, Expression of IFNGR1 in Treg cells from uninfected Foxp3Cre-YFP (n = 7) and Ifngr1L/LFoxp3Cre-YFP (n = 5) mice was measured by flow cytometry. c, d, Foxp3Cre-YFP mice remained uninfected (n = 15, 5 independent experiments, control; n = 10, 4 independent experiments, Ifngr1-deficient) or were infected with Arm. (n = 9, 2 independent experiments, control; n = 8, 2 independent experiments, Ifngr1-deficient) or Cl. 13 (n = 15, control; n = 14 (c), n = 15 (d), Ifngr1-deficient) and percentage of Foxp3+ of CD4+ T cells (c), number of Treg cells (d, upper) and CD4+ Tconv cells (d, lower) per spleen, were determined by flow cytometry. e-g, scRNA-seq of splenic Treg cells from uninfected (n = 3) or Cl. 13 infected (n = 5) (d16) Foxp3Cre-YFP or Ifngr1L/LFoxp3Cre-YFP mice. e, Distribution of cells amongst clusters. f, Top 50 ranked significant differentially expressed genes from Treg cells in Foxp3Cre-YFP and Ifngr1L/LFoxp3Cre-YFP mice infected with Cl. 13. g, GSEA overview illustrating pathways upregulated in the control Treg cell gene set compared to Ifngr1-deficient Treg cells during Cl. 13 infection. h, Foxp3Cre-YFP or Ifngr1L/LFoxp3Cre-YFP mice remained uninfected and the expression of T-bet (n = 7), GATA-3 (n = 6, control; n = 5, Ifngr1-deficient) and RORγt (n = 3, control; n = 4, Ifngr1-deficient) by splenic Treg cells were measured by flow cytometry. a-h, Data are presented as mean values and represents biologically independent mice and 2 (a, b, e-h and as indicated) or 3 (c, d) or 5 (as indicated) independent experiments. Statistical significance was determined by an unpaired two-tailed Student’s t-test (b), or by multiple unpaired t-tests (a, c, d, h), relative to Foxp3Cre-YFP mice. Adjusted P values were determined by one-way ANOVA relative to Foxp3Cre-YFP mice (e) or by Wilcoxon rank-sum test (f) or Kolmogorov-Smirnov test (g) relative to infected Foxp3Cre-YFP mice (P values indicated when significant); NS, not significant.

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Extended Data Fig. 4 Intrinsic effects of Ifngr1 deletion from Treg cells using Ifngr1L/LFoxp3Cre-YFPFoxp3Cre-ERT2-GFP heterozygous mice.

a-e, Heterozygous Foxp3Cre-YFP.Foxp3Cre-ERT2-GFP (Cre Het) (n = 5, Uninfected; n = 12, Cl. 13) and Ifngr1L/LFoxp3Cre-YFP.Foxp3Cre-ERT2-GFP (L/L Het) (n = 10, Uninfected; n = 19, Cl. 13) female mice remained uninfected (2 independent experiments) or were infected with Cl. 13 (3 independent experiments). a, Percent expression of GFP+ and YFP+ by splenic CD4+ T cells were determined by flow cytometry. b-e, Expression of the CXCR3 (b), CCR4 (c), CD127 (d) and KLRG1 (e) in splenic Treg cells from indicated mice were measured by flow cytometry. f-h, Heterozygous Foxp3Cre-YFP.Foxp3Cre-ERT2-GFP (Cre Het) and Ifngr1L/LFoxp3Cre-YFP.Foxp3Cre-ERT2-GFP (L/L Het) female mice were infected with Cl. 13. f, Gating strategy for IFNGR1– and IFNGR1+ splenic Treg cells (g, h) from indicated mice. g, h, Expression of T-bet (g) (n = 10, Cre HET; n = 15, L/L HET) and GATA-3 (h) (n = 10, Cre HET; n = 12, L/L HET) by IFNGR1– and IFNGR1+ splenic Treg cells from indicated mice, were measured by flow cytometry. a-h, Data are presented as mean values and represent biologically independent mice and 2 (as indicated) or 3 (a-e, g, h and as indicated) independent experiments. Statistical significance was determined by a two-way AVOVA with multiple comparisons (a, g, h) or by one-way AVOVA with multiple comparisons (b-e) (P values indicated when significant); NS, not significant.

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Extended Data Fig. 5 Treg cells maintain stability during chronic infection.

a, DE of genes induced (upper), or repressed (lower), by Foxp3 in splenic Treg cells of Foxp3Cre-YFP mice compared to Ifngr1L/LFoxp3Cre-YFP mice, that remained uninfected (n = 3) or were infected with Cl. 13 (n = 5) was measured by scRNA-seq. b, c Foxp3Cre-ERT2-GFPRosa26LSL.tdTom mice were treated with tamoxifen for 7d and then remained uninfected or were infected with Cl. 13. b, Experimental schema. c, Representative flow cytometry plot of tdTom and GFP co-expression in splenic CD4+ T cells at steady state (n = 7) or at 16 (n = 5, 2 independent experiments) and 35 (n = 11, 2 independent experiments) dpi with Cl. 13. d-f, Foxp3Cre-YFP or Ifngr1L/LFoxp3Cre-YFP mice were infected with Cl. 13 and levels of Foxp3 (d) (n = 9, control; n = 10, Ifngr1-deficient) and percentage of Nrp1 (e) (n = 9, control; n = 8, Ifngr1-deficient) CD25 (f, left) (n = 11) and level of CD25 (f, right) (n = 11) by splenic Treg cells were determined by flow cytometry. a, c-f, Data are presented as mean values and represent biologically independent mice and 2 (a, d-f and as indicated) or 3 (c) independent experiments. Statistical significance was determined by an unpaired two-tailed Student’s t-test relative to Foxp3Cre-YFP mice (d-f). Adjusted P value was determined by Wilcoxon rank-sum test (a) (P value indicated when significant); NS, not significant.

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Extended Data Fig. 6 IFNγ promotes TH1-like polarization of Treg cells during Influenza A viral infection.

a-d, Foxp3Cre-YFP or Ifngr1L/LFoxp3Cre-YFP mice were infected with IAV. a, b, Percentage of initial body weight over time (a) (numbers of mice used indicated in parentheses) and at day 6 (b) (n = 16, control; n = 17, Ifngr1-deficient). c, d, Expression of T-bet (c) (n = 9, control; n = 7, Ifngr1-deficient) and GATA-3 (d) (n = 10, control; n = 8, Ifngr1-deficient) by lung Treg cells were measured by flow cytometry. a-d. Data are presented as mean values and represent biologically independent mice and 2 (a, c, d) or 3 (b) independent experiments. Statistical significance was determined by two-way ANOVA with multiple comparisons (a) or by an unpaired two-tailed Student’s t-test (b-d), all relative to Foxp3Cre-YFP mice (P values indicated when significant); NS, not significant.

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Extended Data Fig. 7 Ifngr1 deletion from Treg cells does not affect viral load nor markers associated with CD8+ T cell exhaustion during chronic infection.

a, b, Foxp3Cre-YFP, Ifngr1L/L or Ifngr1L/LFoxp3Cre-YFP mice remained uninfected or were infected with Cl. 13. a, Liver histological score from uninfected mice (n = 2) or mice infected with Cl. 13 8 dpi (n = 4, Foxp3Cre-YFP; n = 3, Ifngr1L/L; n = 3, Ifngr1L/LFoxp3Cre-YFP). Score determined as: 1= Triaditis, rare sinusoidal lymphocytes; 2= Triaditis, prominent sinusoidal lymphocytes; 3= Triaditis, prominent sinusoidal lymphocytes, single cell apoptosis. b, Serum AST activity was determined in uninfected mice (n = 9, Foxp3Cre-YFP; n = 2, 1 independent experiment, Ifngr1L/L; n = 8, Ifngr1L/LFoxp3Cre-YFP) or mice infected with Cl. 13, 8 dpi (n = 13, Foxp3Cre-YFP; n = 14, Ifngr1L/LFoxp3Cre-YFP) or 16 dpi (n = 10, Foxp3Cre-YFP; n = 2, 1 independent experiment, Ifngr1L/L; n = 9, Ifngr1L/LFoxp3Cre-YFP). c, Foxp3Cre-YFP or Ifngr1L/LFoxp3Cre-YFP mice were infected with Cl. 13 and the viral load in serum d16 (n = 12, control; n = 11, Ifngr1-deficient; 2 independent experiments) and d30 (n = 11, control; n = 10, Ifngr1-deficient; 2 independent experiments), kidney (n = 7, control; n = 6, Ifngr1-deficient; 1 independent experiment) and liver (n = 5, control; n = 3, Ifngr1-deficient; 1 independent experiment) were determined. d, Foxp3Cre-YFP or Ifngr1L/LFoxp3Cre-YFP mice were infected with Cl. 13 and treated with 200 µg isotype control (n = 3, control; n = 4, Ifngr1-deficient) or anti-PDL1 (n = 5, control; n = 2, Ifngr1-deficient) every 3 d from 26-38 dpi and the viral load in kidney was determined. e, f, Foxp3Cre-YFP (n = 19) or Ifngr1L/LFoxp3Cre-YFP (n = 16) mice were infected with Cl. 13 and IR co-expression (indicated on top) with PD1 (e), and SPICE plots visualizing multiple combinations of IR co-expression (f), by pooled Tetramer+ (GP33, GP276, NP396) splenic CD8+ T cells were determined by flow cytometry. g-j, Foxp3Cre-YFP or Ifngr1L/LFoxp3Cre-YFP mice were infected with Cl. 13 and treated with isotype control (n = 7) or anti-PDL1 (n = 6, control; n = 8, Ifngr1-deficient) as in (d). g, h, Expression of T-bet by bulk splenic CD8+ T cells (g) and PD1 by pooled Tetramer+ (GP33, GP276, NP396) splenic CD8+ T cells (h) were determined by flow cytometry. i, Percentage of pTex (Tcf1+TIM3–) and tTex (TCF1–TIM3+) splenic CD8+ T cells were determined by flow cytometry. j, Percentage of tTex splenic GP33+CD8+ T cells was determined by flow cytometry. a-j, Data are presented as mean values and represent biologically independent mice and 1 (a, d, and as indicated), 2 (c, g-j) or 3 (b, e, f) independent experiments. a-e, g-j, Statistical significance was determined by a two-way ANOVA with multiple comparisons (a, b) or by an unpaired two-tailed Student’s t-test relative to Foxp3Cre-YFP mice (c, e) or my multiple unpaired Student’s t-tests (d, g-j) (P values indicated when significant); NS, not significant.

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Extended Data Fig. 8 Ifngr1-deficient Treg cells from infected mice maintain suppressive function of naïve CD4+ Tconv cells in vitro and do not impact TH polarization of CD4+ Tconv cells in vivo.

a,b, In vitro microsuppression assay of splenic uninfected CD4+ Tconv (Tresponders) by splenic Treg cells from Foxp3Cre-YFP or Ifngr1L/LFoxp3Cre-YFP mice infected with LCMV Arm. (a) or Cl. 13 (b) (numbers of mice used indicated in parentheses). c, In vitro microsuppression assay of splenic CD44hiCD62Llo CD4+ Tconv (Teff) from Arm. infected Foxp3Cre-YFP mice by splenic Treg cells from Foxp3Cre-YFP or Ifngr1L/LFoxp3Cre-YFP mice infected with LCMV Arm. (numbers of mice used indicated in parentheses). d-g, Foxp3Cre-YFP or Ifngr1L/LFoxp3Cre-YFP mice infected with Cl. 13 and expression of T-bet, GATA-3 and RORγt (d) (n = 8), T-bet and GATA-3 co-expression (e) (n = 8), CXCR3 (f) (n = 8) and CCR4 (g) (n = 8, control; n = 9, Ifngr1-deficient) by splenic CD4+ Tconv cells were measured by flow cytometry. h, Expression of the deleted region of Ifng, normalized to the intact region of Ifng, from IfngL/LFoxp3Cre-YFP mice (n = 4) compared to Foxp3Cre-YFP mice (n = 3). Thy1.2– cells, CD8+ T cells, CD4+ Tconv cells and Treg cells were sorted, gDNA was isolated and qPCR was performed. a-h Data are presented as mean values and represent biologically independent mice and 1 (h), 2 (b-g) or 3 (a) independent experiments. Statistical significance was determined by two-way ANOVA (a-c), or by multiple unpaired Student t-tests (d, e, h), or by an unpaired two-tailed Student’s t-test (f, g), relative to Foxp3Cre-YFP mice (P values indicated when significant); NS, not significant.

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Extended Data Fig. 9 Transcriptomic analysis reveals that TH1-like Treg cells inhibit CD8+ T cell memory during LCMV infection.

a-c, scRNA-seq of splenic pooled Tetramer+ (GP33, GP276, NP396) CD8+ T cells from Foxp3Cre-YFP or Ifngr1L/LFoxp3Cre-YFP mice (n = 3), 16 dpi with Cl. 13. a, UMAP embedding Tetramer+ CD8+ T cells into a two-dimensional space to generate 8 distinct clusters, with categories shown. b, Distribution of cells amongst clusters from individual mice. c, Percentage of cells in the memory cluster. d, e, Foxp3Cre-YFP or Ifngr1L/LFoxp3Cre-YFP mice were infected with Arm. and the expression of effector CD8+ cells (d) (n = 18, control; n = 16, Ifngr1-deficient) and the ratio of MPECs to SLECs within splenic pooled CD44hiCD62Llo Tetramer+ CD8+ T cells (e) (n = 8) were determined by flow cytometry. f, g, Expression of Ifngr1 within the bulk population (f) and within the memory cluster (g) of the splenic pooled Tetramer+ CD8+ T cells from the scRNA-seq dataset in a-c (n = 3). h-j, Rag1–/– mice were reconstituted with Ifngr1–/– (n = 12) or control (WT) (n = 13) Treg cells and infected with Arm. h, i, Frequency of splenic CD44hiCD62Llo (h) and CD44hiCD62Lhi (i, left), and number of CD44hiCD62Lhi (i, right) pooled Tetramer+ CD8+ T cells were determined by flow cytometry. j, Frequency of (left) and total number of (right) MPECs (upper) and SLECs (lower), and the ratio of MPECs to SLECs, splenic pooled Tetramer+ CD8+ T cells were determined by flow cytometry. k, heatmap of DE of the IL16/CD4/CCR5 signaling axis in Treg cells from the scRNA-seq dataset in a-c. l-n, Foxp3Cre-YFP and Ifngr1L/LFoxp3Cre-YFP mice were infected with Arm. and transcripts of the IL16/CD4/CCR5 signaling axis in Treg cells (l) (n = 11) or Il16 (m) (n = 11) and Ccl5 (n) (n = 6, control; n = 9, Ifngr1-deficient) expression in Treg cells and CD44hiCD62Llo CD4+ and CD8+ T cells, were determined by qPCR. a-n, Data are presented as mean values and represent biologically independent mice and 1 (a-c, f, g), 2 (e, k, n) or 3 (d, h-j, l, m) independent experiments. Statistical significance and P values were determined by an unpaired two-tailed Student’s t-test relative to the Foxp3Cre-YFP mice (c-g) or Rag1–/– + WT Treg cells (h-j), or by multiple unpaired Student t-tests relative to Foxp3Cre-YFP mice (l) or by two-way ANOVA with multiple comparisons. (m,n), Adjusted P values were determined by one-way ANOVA (b) or Wilcoxon rank-sum test (k) relative to infected Foxp3Cre-YFP mice (P values indicated when significant); NS, not significant.

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Extended Data Fig. 10 TH1-like Treg cells do not impact tissue resident memory CD8+ T during IAV infection rechallenge.

a-g, Foxp3Cre-YFP or Ifngr1L/LFoxp3Cre-YFP mice were infected with PR8 only (n = 9, control; n = 8, Ifngr1-deficient) or X31 and challenged with PR8 (n = 10, control; n = 9, Ifngr1-deficient). a, Experimental schema. b, Expression of LAP/TGFβ1 by lung Treg cells by percent (upper) and level of expression within LAP/TGFβ1+ Treg cells (lower) were determined by flow cytometry. c, Percentage (upper), and number (lower), of lung IAV pooled Tetramer+ (PA224 and NP366) CD8+ T were determined by flow cytometry. d, Expression of IFNγ by lung CD8+ T cells was measured, after in vitro stimulation with pooled IAV peptides (PA224-233 and NP366-372), by flow cytometry. e, Expression of CXCR3 by lung pooled Tetramer+ CD8+ T cells was measured by flow cytometry. f, Percentage (left), and number (lower), of CD103+CD69+ lung pooled Tetramer+ CD8+ T cells were determined by flow cytometry. g, Blinded histology scores (areas indicated) of paraffin-embedded hematoxylin and eosin stained, lung tissue sections. b-g, Data are presented as mean values and represent biologically independent mice and 3 independent experiments. Statistical significance was determined by multiple unpaired Student’s t-tests relative to Foxp3Cre-YFP mice (P values indicated when significant); NS, not significant.

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Gocher-Demske, A.M., Cui, J., Szymczak-Workman, A.L. et al. IFNγ-induction of TH1-like regulatory T cells controls antiviral responses. Nat Immunol 24, 841–854 (2023). https://doi.org/10.1038/s41590-023-01453-w

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