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Our Science

Immune regulatory circuits in cancer, autoimmunity, and inflammatory disease.

Over 30 years, the Vignali Laboratory has defined how immune regulatory pathways and T cell signaling programs shape cancer, autoimmunity, and inflammatory disease. These stories connect mechanistic mouse models, patient samples, systems immunology, and enabling technologies to translational immunology.

01

Inhibitory Receptors - LAG3, and more recently PD1 and NRP1

The Vignali Lab has been instrumental in studying the inhibitory receptor LAG3 for the last 25 years. Our lab first showed that LAG3 regulates Treg activity and function, demonstrated that LAG3 and PD1 cooperate to limit T cell function and promote tumor immune escape, and more recently defined how LAG3 restrains TCR-CD3 signaling, CD8+ T cell exhaustion, and patient responses to LAG3/PD1 blockade.

Selected publications

  1. Huang C-T et al. (2004). Role of LAG-3 in regulatory T cells. Immunity.
  2. Woo S-R*, Turnis ME*, Goldberg MV* et al. (2012). Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T cell function to promote tumoral immune escape. Cancer Research.
  3. Zhang Q et al. (2017). LAG-3 limits regulatory T cell proliferation and function in autoimmune diabetes. Science Immunology.
  4. Liu C et al. (2020). Neuropilin-1 is a T cell memory checkpoint limiting long-term anti-tumor immunity. Nature Immunology.
  5. Andrews LP et al. (2020). Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding. Science Immunology.
  6. Guy C et al. (2022). LAG3 associates with TCR-CD3 complexes and suppresses signaling by driving co-receptor-Lck dissociation. Nature Immunology.
  7. Grebinoski S*, Zhang Q* et al. (2022). Autoreactive CD8+ T cells are restrained by a divergent exhaustion program. Nature Immunology.
  8. Andrews LP*, Butler SC* et al. (2024). LAG3 and PD1 synergize on CD8+ T cells to drive T cell exhaustion and hinder autocrine IFNg-dependent anti-tumor immunity. Cell.
  9. Cillo AR et al. (2024). Relatlimab plus nivolumab rewires dysfunctional CD8+ T cells by coupling cytotoxic and exhaustion gene modules to promote antitumor immunity. Cell.
02

Regulatory T cells - mechanisms that mediate suppression

A major focus of the Vignali Lab for over 15 years has been the identification and dissection of pathways that mediate and control Treg function, especially pathways used in tumors as potential targets for immunotherapy. Our lab discovered IL-35, showed that it can induce a potent regulatory T cell population, defined its unconventional receptor, and linked IL35+ and IL10+ Treg programs to intratumoral T cell exhaustion.

Selected publications

  1. Collison LW et al. (2007). The inhibitory cytokine IL-35 contributes to regulatory T cell function. Nature.
  2. Collison LW et al. (2010). Interleukin-35-mediated induction of a potent regulatory T cell population. Nature Immunology.
  3. Collison LW*, Delgoffe GM* et al. (2012). The composition and signaling of the IL-35 receptor are unconventional. Nature Immunology.
  4. Turnis ME*, Sawant DV* et al. (2016). Interleukin-35 limits anti-tumor immunity. Immunity.
  5. Sawant DV*, Yano H* et al. (2019). Adaptive plasticity of IL10+ and IL35+ regulatory T cells cooperatively promote intratumoral T cell exhaustion. Nature Immunology.
03

Regulatory T cells - mechanisms that control function and stability

A second major discovery from the Vignali Lab centers on pathways that control Treg stability and function. Our lab identified a neuropilin-1:semaphorin-4a pathway that maintains intratumoral Treg stability, function, and survival, showed that IFNg can drive Treg fragility to promote anti-tumor immunity, and connected intratumoral Treg states with cancer outcomes and immune control in infection.

Selected publications

  1. Collison LW et al. (2009). Regulatory T cell suppression is potentiated by target T cells in a cell contact, IL-35- and IL-10-dependent manner. Journal of Immunology.
  2. Delgoffe GM*, Woo S-R* et al. (2013). Stability and function of regulatory T cells is maintained by a neuropilin-1:semaphorin-4a axis. Nature.
  3. Overacre-Delgoffe AE et al. (2017). Interferon-gamma drives Treg fragility to promote anti-tumor immunity. Cell.
  4. Liu C et al. (2019). Treg cells promote the SREBP1-dependent metabolic fitness of M2-like intratumoral macrophages via CD8+ T cells. Immunity.
  5. Chuckran CA et al. (2021). Prevalence of intratumoral regulatory T cells expressing neuropilin-1 is associated with poorer outcomes in patients with cancer. Science Translational Medicine.
  6. Shan F et al. (2023). Integrated BATF transcriptional network regulates suppressive intratumoral regulatory T cells. Science Immunology.
  7. Gocher-Demske AM et al. (2023). Interferon gamma-induction of TH1-like regulatory T cells controls anti-viral responses. Nature Immunology.
04

T Cell Receptor:CD3 signaling and function

The Vignali Lab has a long-standing interest in TCR:CD3 complex signaling and function, including cell trafficking, regulation of cell-surface expression, signaling mechanisms, and the contribution of CD3 ITAMs to different T cell functions. This work continues to inform how inhibitory receptors intersect with core TCR signaling machinery.

Selected publications

  1. Liu HY et al. (2000). On the dynamics of TCR:CD3 complex cell surface expression and downmodulation. Immunity.
  2. Holst J et al. (2008). Scalable signaling mediated by T cell antigen receptor-CD3 ITAMs ensures effective negative selection and prevents autoimmunity. Nature Immunology.
  3. Guy C et al. (2013). Distinct TCR signaling pathways drive proliferation and cytokine production in T cells. Nature Immunology.
05

Systems immunology

Our lab has incorporated transcriptional analysis into its research for over a decade and has expanded systems immunology expertise through single-cell transcriptomic approaches and computational tools. These studies map immune states in human cancers and connect pathway biology to disease context.

Selected publications

  1. Cillo AR et al. (2020). Immune landscape of viral- and carcinogen-driven head and neck cancer. Immunity.
  2. Onkar SS et al. (2022). Immune landscape in invasive ductal and lobular breast cancer reveals a divergent macrophage-driven microenvironment. Nature Cancer.
06

Innovation

The Vignali Lab was among the first groups to develop bead-based multiplexed cytokine assays using Luminex systems and helped popularize 2A peptide-based self-cleaving multicistronic expression systems. These methods enabled TCR retrogenic mice, viral-vector strategies, and broader adoption of multi-gene expression technologies in immunology.

Selected publications

  1. Carson RT & Vignali DAA (1999). Simultaneous quantitation of fifteen cytokines using a multiplexed flow cytometric assay. Journal of Immunological Methods.
  2. Szymczak AL et al. (2004). Correction of multi-gene deficiency in vivo using a single self-cleaving 2A peptide-based retroviral vector. Nature Biotechnology.
  3. Holst J et al. (2006). Rapid analysis of T cell selection and function in vivo using T cell receptor retrogenic mice. Nature Methods.
  4. Andrews LA et al. (2021). A Cre-driven allele-conditioning line to interrogate CD4+ conventional T cells. Immunity.
07

Highly cited reviews

The Vignali Lab has contributed several highly cited and invited reviews that synthesize major areas of immunology, including regulatory T cell function, IL-12 family cytokines, interferon-gamma biology in tumors, LAG3 checkpoint biology, T cell exhaustion, and Tregs in the tumor microenvironment.

Selected publications

  1. Vignali DAA, Collison LW, Workman CJ (2008). How regulatory T cells work. Nature Reviews Immunology.
  2. Vignali DAA, Kuchroo VK (2012). IL-12 Family Cytokines: Immunological Playmakers. Nature Immunology.
  3. Gocher AM, Workman CJ, Vignali DAA (2021). Interferon gamma: teammate or opponent in the tumour microenvironment? Nature Reviews Immunology.
  4. Aggarwal V, Workman CJ, Vignali DAA (2023). LAG3 as the third checkpoint inhibitory. Nature Immunology.
  5. Baessler A, Vignali DAA (2024). T Cell Exhaustion. Annual Review of Immunology.
  6. Imianowski CJ*, Chen Q*, Workman CJ, Vignali DAA (2025). The role of regulatory T (Treg) cells in the tumor microenvironment. Nature Reviews Cancer.