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A septin requirement differentiates autonomous and contact-facilitated T cell proliferation

Nature Immunology volume 17, pages 315–322 (2016)Cite this article

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Abstract

T cell proliferation is initiated by T cell antigen receptor (TCR) triggering, soluble growth factors or both. In characterizing T cells lacking the septin cytoskeleton, we found that successful cell division has discrete septin-dependent and septin-independent pathways. Septin-deficient T cells failed to complete cytokinesis when prompted by pharmacological activation or cytokines. In contrast, cell division was not dependent on septins when cell-cell contacts, such as those with antigen-presenting cells, provided a niche. This septin-independent pathway was mediated by phosphatidylinositol-3-OH kinase activation through a combination of integrins and costimulatory signals. We were able to differentiate between cytokine- and antigen-driven expansion in vivo and thus show that targeting septins has strong potential to moderate detrimental bystander or homeostatic cytokine-driven proliferation without influencing expansion driven by conventional antigen-presentation.

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Figure 1: Septin-deficient T cells exhibit selective cytokinetic defects upon APC-independent stimulation.
Figure 2: Septin-deficient T cells undergo cytokinetic failure after cytokine exposure.
Figure 3: APCs mediate rescue of septin-null CD8+ T cell cytokinetic defect through costimulatory PI(3)K signaling.
Figure 4: Costimulatory signaling is sufficient to enhance septin-null CD8+ T cell division.
Figure 5: Septin deficiency differentiates APC- and cytokine-driven division in vivo.
Figure 6: Septins are required for homeostatic maintenance of naive and memory CD8+ T cells in vivo.

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Acknowledgements

We thank the Biological Imaging Development Center personnel (UCSF) for technical assistance with imaging, J. Roose and O. Ksionda (UCSF) for reagents and helpful discussion, E. Palmer (University Hospital Basel and University of Basel) and D. Zehn (Swiss Vaccine Research Institute and Lausanne University Hospital) for reagents, and M. Kuhns (University of Arizona College of Medicine) for critical reading of the manuscript. Supported by the US National Institutes of Health (R01AI52116 to (M.F.K).

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  1. Julia K Gilden

    Present address: Present address: Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.,

Authors and Affiliations

  1. Department of Pathology, University of California, San Francisco, San Francisco, California, USA.,

    Adriana M Mujal, Julia K Gilden, Audrey Gérard & Matthew F Krummel

  2. Division of Biological Sciences, Nagoya University Graduate School of Science, Nagoya, Japan

    Makoto Kinoshita

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Contributions

A.M.M. and M.F.K. designed the experiments for all primary text figures; A.M.M. did experiments; J.K.G. performed and helped with experiments related to initial characterization of Sept7cKO mice; A.G. contributed to experimental design and analysis; M.K. provided the Sept7flox/flox mice and consulted on experiments; A.M.M. and M.F.K. wrote and revised the manuscript.

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Correspondence to Matthew F Krummel.

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Integrated supplementary information

Supplementary Figure 1 Septin-deficient T cells develop similarly to wild-type T cells.

(a) Intracellular Septin 7 protein expression by polyclonal CD4+ and CD8+ T cells from Sept7cKO or control mouse spleen as assessed by flow cytometry. (b) Protein levels of septin family members determined by Western blots of isolated CD8+ T cells from Sept7cKO or control OT-I mouse spleens. (c, d) Intracellular septin 7 expression (c) and frequency (d) of thymocyte populations from the thymus of Sept7cKO or control mice. (e, f) Cellularity of secondary lymphoid organs (e) and frequency of peripheral lymphocytes in lymph nodes (f) of Sept7cKO or control mice. (g) Intracellular phalloidin levels of naïve polyclonal CD8+ Sept7cKO or control T cells as tested with flow cytometry. (h, i) Activated Sept7cKO and control OT-I cells were plated on ICAM-1-coated coverslips and imaged for morphological measurements. Images of control and Sept7cKO cells illustrating the elongated uropod of Sept7cKO cells (h). Quantification of measurements and population distribution of cell length (i). Data is representative of two (h, i), three (a-c, e), or five (d, f) independent experiments. Small horizontal bars denote the SEM. *P <0.05 with data analyzed with unpaired t-test (e).

Supplementary Figure 2 Septin-deficient CD8+ T cell multinucleated cell formation is associated with an increase in size, despite similar initial F-actin levels and normal activation.

(a-f) Sept7cKO or control CD8+ OT-I T cells were cultured in vitro with SL8-pulsed (100ng/ml) BMDCs, on plate-bound anti-CD3 or anti-TCR with soluble anti-CD28, or with PMA and ionomycin. Quantification of mean CFSE dilution peak number of live activated Sept7cKO and control OT-I cells 72h after a designated in vitro condition (a). Frequency of live CD8+ cells from Sept7cKO or control OT-I mice with a given DNA content level as assessed by Hoechst with flow cytometry 72h following in vitro activation (b). Comparison of cellular forward-scatter area and intracellular Septin 7 within activated CD8+ T cells isolated from Sept7cKO OT-I lymph nodes 72h after in vitro activation. Gating delineates a population of septin-competent T cells in Sept7cKO mice (c). F-actin levels in Sept7cKO and control CD8+ OT-I T cells 24h following in vitro activation (d). Cell surface CD69 (e) and CD25 (f) expressed by CD8+ OT-I T cells 24h after activation. (g) Calcium flux in isolated naïve CD8+ OT-I T cells following stimulation by anti-CD3 clustering (top) or thapsigargin stimulation (bottom). The average of technical duplicate or triplicate samples for a given experiment and condition was calculated and graphed (a, b). Data is pooled from at three (a), six (b, right), seven (b, middle), or ten (b, left) independent experiments, or representative of three independent experiments (c-g). Small horizontal bars denote the SEM. *P <0.05, **P<0.01, ***P< 0.001, ****P< 0.0001 with data analyzed with unpaired t-test (a, b).

Supplementary Figure 3 Septin-null T cell division is enhanced by costimulatory but not cytokine signaling.

(a-d) Sept7cKO and control OT-I T cells were stimulated in vitro and the mean CFSE peak number of live cells was quantified. Analysis of cell proliferation 5d after exposure in vitro to IL-7 (5ng/ml) and IL-15 (100ng/ml), or IL-2 (5000U/ml) (a), 72h after PMA/iono or anti-TCR activation with or without the presence of low-dose IL-2 (10-20U/ml) (b), 72h after PMA/iono activation in the presence of plate-bound Fc-ICAM, fibronectin, anti-CD44, or anti-CD28 (c), or 48h following PMA/iono stimulation in conjunction with plate-bound Fc-ICAM for a designated temporal duration (d). The average of technical duplicate or triplicate samples was calculated and graphed. Small horizontal bars represent the SEM. Data is pooled from three (a, b) or four (c, d) independent experiments. *P< 0.05, **<P 0.01, ***P< 0.001 with data analyzed with unpaired (a, c), or paired (b) t-test, or a matched one-way ANOVA test with Fisher’s LSD post-test (d).

Supplementary Figure 4 BMDCs mediate septin-deficient T cell division through PI(3)K costimulatory signaling.

(a-e) Sept7cKO (red) and control (black) OT-I live activated cell mean CFSE dilution peak number was calculated following in vitro activation. Quantification of T cell CFSE dilution 72h following PMA/iono activation with addition of antigen-free or SL8-pulsed (100ng/ml) BMDCs, or supernatant from BMDC-T cell culture (a), 72h following PMA/iono activation with addition of antigen-free BMDCs and designated blocking antibody 0h (left) or 24h (right) after plating (b), 72h following PMA/iono activation with addition of antigen-free BMDCs and PI(3)K inhibitor LY294,002 (10μM) (left) or GDC-0941 (10μM) (right) (c), or 72h following activation with SL8-pulsed (1-100ng/ml) BMDCs with addition of PI(3)K inhibitor LY244,022 (10μM) or GDC-0941 (10μM) 36h (d) or 24h (e) after plating. The average of technical duplicate samples was calculated and graphed. Small horizontal bars denote the SEM. Data is pooled from three (a, d, e), five (b, c, left), or six (c, right) independent experiments. *P< 0.05, **<P 0.01, ***P< 0.001, ****P <0.0001 with data analyzed with an unmatched one-way ANOVA test with Fisher’s LSD post-test.

Supplementary Figure 5 LPS-treated B cells enhance septin-null CD8+ T cell division through costimulatory PI(3)K signaling.

(a) Cell surface expression of CD69 by Sept7cKO or control CD8+ OT-I T cells following 24h of co-culture with SL8-pulsed (100ng/ml) resting or LPS-treated B cells. (b) Quantification of Sept7cKO and control OT-I live cell mean CFSE peak number 72h following in vitro co-culture with resting or LPS-treated B cells and addition of blocking antibodies against CD80, CD86, and/or LFA-1, or PI(3)K inhibitor LY294,002 (10μM). The average of technical duplicate samples was calculated and graphed. Small horizontal bars denote the SEM. (c) CFSE dilution of Sept7cKO or control CD8+ OT-I T cells 72h after in vitro activation by resting or LPS-treated B cells and addition of denoted blocking antibodies, or PI(3)K inhibitor LY294,002 (10μM). Data is representative of three (a, b, right), or four (b, left) experiments. *P< 0.05, **P< 0.01, ***P< 0.001, ****P <0.0001 with data analyzed with an unmatched one-way ANOVA test with Fisher’s LSD post-test (b).

Supplementary Figure 6 Homeostatic maintenance of septin-deficient and control CD8+ memory T cells in the lymph node.

(a-c) Sept7cKO and control OT-I T cells were transferred to DecOVA-immunized mice, sorted from the spleen and lymph nodes 14d later, and co-transferred to antigen-free host mice. Ratio of control to Sept7cKO OT-I T cells sorted from lymph nodes 14d post-DecOVA immunization. *P value = 0.0107 with data analyzed with 1-sample t-test comparing distribution to theoretical mean of 1 (a). Surface expression of CD44 and CD62L on Sept7cKO and control OT-I T cells sorted from pooled spleen and lymph nodes 14d post-DecOVA immunization (b). Ratio of control to Sept7cKO OT-I T cells recovered from pooled skin-draining lymph nodes 8 weeks following co-transfer to antigen-free hosts. Non-significant P value (> 0.05) with data analyzed with 1-sample t-test comparing distribution to theoretical mean of 1 (c). Each symbol represents an individual experiment (a) or mouse (c). Small horizontal lines demarcate the SEM. Data is pooled from four (c) or five (a) independent experiments with total n = 5 (a) or 6 (c), or representative of two independent experiments (b).

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Mujal, A., Gilden, J., Gérard, A. et al. A septin requirement differentiates autonomous and contact-facilitated T cell proliferation. Nat Immunol 17, 315–322 (2016). https://doi.org/10.1038/ni.3330

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