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Innate-like T cells straddle innate and adaptive immunity by altering antigen-receptor responsiveness

Nature Immunology volume 15, pages 80–87 (2014)Cite this article

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Abstract

The subclassification of immunology into innate and adaptive immunity is challenged by innate-like T lymphocytes that use innate receptors to respond rapidly to stress despite expressing T cell antigen receptors (TCRs), a hallmark of adaptive immunity. In studies that explain how such cells can straddle innate and adaptive immunity, we found that signaling via antigen receptors, whose conventional role is to facilitate clonal T cell activation, was critical for the development of innate-like T cells but then was rapidly attenuated, which accommodated the cells' innate responsiveness. These findings permitted the identification of a previously unknown innate-like T cell subset and indicate that T cell hyporesponsiveness, a state traditionally linked to tolerance, may be fundamental to T cells entering the innate compartment and thereby providing lymphoid stress surveillance.

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Figure 1: SKG mice are severely depleted of IL-17A-producing γδ T cells.
Figure 2: The loss of IL-17A-producing γδ T cells in SKG mice is developmental.
Figure 3: CD27− γδ cells are hyporesponsive to TCR stimulation.
Figure 4: Atypical TCR responses of DETCs and their progenitors.
Figure 5: CD27+CD45RBhi γδ cells are innate-like T cells.

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Acknowledgements

We thank S. Sakaguchi (Osaka University) for SKG mice; K. Hogquist (University of Minnesota) for Nur77-GFP mice; and our colleagues, including M.-L. Michel, P. Vantourout, O. Sobolev, R. Hart, M. Swamy, B. Silva-Santos, D. Pennington, G. LeClercq, P. Parker and M. Saini and the staff of the flow cytometry and biological services units of the London Research Institute and of the Peter Gorer Department of Immunobiology, King's College London, for help and discussions. Supported by Cancer Research UK, Marie Curie Actions (L.D.), the University College London MBPhD programme (R.D.M.B.) and the Wellcome Trust (A.C.H.).

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Author notes

  1. Gleb Turchinovich

    Present address: Present address: Department of Biomedicine, University of Basel, Basel, Switzerland.,

  2. Melanie Wencker and Gleb Turchinovich: These authors contributed equally to this work.

Authors and Affiliations

  1. London Research Institute, Cancer Research UK, London, UK

    Melanie Wencker, Gleb Turchinovich, Rafael Di Marco Barros, Livija Deban, Anett Jandke & Adrian C Hayday

  2. Peter Gorer Department of Immunobiology, King's College London, London, UK

    Melanie Wencker, Gleb Turchinovich & Adrian C Hayday

  3. University College London, London, UK

    Rafael Di Marco Barros

  4. Centre for the Molecular and Cell Biology of Inflammation, King's College London, London, UK

    Andrew Cope

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Contributions

M.W. contributed to study design, undertook experiments, analyzed data and contributed to data interpretation and to manuscript preparation and editing; G.T. contributed to study design, undertook experiments, analyzed data and contributed to data interpretation and to manuscript preparation and editing; R.D.M.B. undertook experiments and analyzed data; L.D. undertook experiments, analyzed data and contributed to manuscript editing; A.J. undertook experiments and analyzed data; A.C. contributed to study design and analysis; and A.C.H. designed the study, contributed to data interpretation and wrote and edited the manuscript.

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Correspondence to Adrian C Hayday.

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Integrated supplementary information

Supplementary Figure 1 SKG mice are severely depleted of IL-17A-producing γδ cells.

(a) Absolute numbers of γδ T cells (TCRδ+ CD3+) isolated from indicated organs of wild type (WT) and SKG animals; Error bars are mean ± SD for 3 to 5 experiments (n ≥ 9 per group). (b) Flow cytometry analysis of γδ T cells isolated from the dermis; error bars are mean ± SD for 2 independent experiments (n = 7 per group). (c) Absolute numbers of IL-17A-producing γδ thymocytes (TCRδ+ CD3+) isolated at different time points from WT and SKG animals and stimulated with PMA and ionomycin; results shown mean ± SD (n ≥ 7 per group). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Supplementary Figure 2 CD27- γδ cells are hyporesponsive to TCR stimulation.

(a) LN CD27+ γδ T cells from WT or SKG mice were assessed for intracellular Ca2+ mobilization following stimulation with anti-CD3ɛ (10 μg/mL) followed by SA crosslinking (10 μg/mL); data are representative of 3 independent experiments (n=8 per group). (b) The indicated subsets of WT thymocytes from adult mice were assessed for intracellular Ca2+ mobilization as in (a); data representative of 3 independent experiments (n=11). (c) Neonatal thymocytes from WT animals were assessed for intracellular Ca2+ mobilization as in (a) in CD45+ TCRδ+ Vγ5− CD27+ and CD45+ TCRδ+ Vγ5− CD27− 17D1+ subsets; data representative of 2 independent experiments (n = 4). (d) Cells were cultured as in fig. 3 (d); IL-17A production was assessed in TCRδ+ CD3+ CD27+ subset. (e) WT LN lymphocytes were cultured for 21h with no cytokines or with IL-1β (10 ng/ml) + IL-23 (50 ng/ml) in wells coated with IgG-control or anti-CD3ɛ (10 μg/ml) and in the presence of Cyclosporin A (80 nM) or DMSO control. Brefeldin A (10 μg/ml) was added for the final 5h and IL-17A protein production assessed by intracellular cytometry in the TCRδ+ CD3+ CD27− CD44hi subset; data representative of 2 independent experiments (n = 3 per condition).

Supplementary Figure 3 Developmental changes in the phenotypes of innate-like T cell progenitors.

(a) Flow cytometry of γδ thymocytes (gated on TCRδ+CD3+) from WT embryos at indicated embryonic gestational ages and stained for CD27 and IL-7Rα or IL-1Rα; (n=3). (b) Flow cytometry of γδ fetal thymocytes (gated on TCRδ+Vγ5+) isolated from FVB. WT or Tac embryos at E16 gestational age and stained for Ly49E/F.

Supplementary Figure 4 Phenotypic traits of innate γδ T cells.

(a) Intracellular flow cytometry profile of sorted WT γδ CD27+ CD45RBhi thymocytes after stimulation with PMA + ionomycin and staining for IFN-γ; plots representative of 2 independent experiments (n = 4 per group). (b) Absolute numbers of IFN-γ-producing γδ thymocytes from adult WT or SKG mice after stimulation with PMA + ionomycin; error bars are mean ± SD; 3 independent experiments (n = 8 per group). (c) Flow cytometry of γδ T cells (gated on TCRδ+ CD3+) from LNs of WT or SKG animals stained for CD27, IL-1Rα, IL-18Rα or LAG-3; plots are representative of 2-3 independent experiments (n ≥ 6 per group); the difference in MFI for CD27 in the right panel reflects the fact that the data were collected from different independent experiments. (d) WT LN cells were cultured for 21h with indicated cytokines. Brefeldin A (10 μg/ml) was added for the final 5h and IL-17A and IFN-γ production was assessed by intracellular cytometry. Plots are gated on TCRδ+ CD3+ CD27− subset; data representative of 2 independent experiments (n = 6 per condition). (e) Expression of DGKα, DGKζ and Cbl-b was analysed by RT-PCR. Assay was performed in triplicates, and is representative of two independent experiments. *P < 0.05, **P < 0.01, *** P < 0.001.

Supplementary Figure 5 Assessment of innate-like T cell criteria in T cell subsets.

(a) Absolute numbers of γδ-NKT (TCR δ+ Vγ1+ Vδ6.3+) or iNKT (CD3+ CD1d αGal-cer tetramers+) cells in indicated organs of WT or SKG mice; error bars are mean ± SD; 2-3 independent experiments (n ≥ 4) (b) Spleen or Liver cells from Nur77-GFP reporter mice were cultured overnight with increasing amounts of coated anti-CD3ɛ (0; 0.5; 2.5 and 12.5 μg/ml). GFP expression was assessed by flow cytometry in indicated subsets; data are representative of 2 independent experiments (n ≥ 6). Data on LN γδ27+ cells are from Fig. 2c and 4d to aid comparison. (c) LN or intestinal intra-epithelial T cells from Nur77-GFP reporter mice were cultured for 4 hours on plates coated with increasing amounts of anti-CD3ɛ (0; 0.5; 2.5 and 12.5 μg/ml). GFP expression was assessed by flow cytometry in indicated subsets; data representative of 2 independent experiments (n ≥ 6).

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Wencker, M., Turchinovich, G., Di Marco Barros, R. et al. Innate-like T cells straddle innate and adaptive immunity by altering antigen-receptor responsiveness. Nat Immunol 15, 80–87 (2014). https://doi.org/10.1038/ni.2773

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