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The Savage Lab

Welcome to the Savage Lab

 

 

Regulation of immune tolerance and anti-tumor immunity

research interests

The goal of our research program is to understand the cellular and molecular mechanisms regulating immune tolerance and the immune response to cancer. Current major projects include:

1.  Development and function of tumor-associated regulatory T cells

Foxp3+ regulatory T (Treg) cells are critical for the suppression of autoimmunity and the regulation of immune homeostasis, and are often prevalent in human cancers. Many emerging therapeutic strategies for the treatment of cancer have focused on the modulation or depletion of Tregs concomitant with vaccination or cell transfer, in order to stimulate effective anti-tumor immune responses. Yet despite this intense interest in modulating Tregs in the context of cancer, fundamental questions regarding the biology of tumor-associated Tregs remain unanswered. Specifically, the developmental origins, antigen specificity, and in situ function of tumor-infiltrating Tregs are not well understood.  Using mouse models of prostate cancer (Malchow et al Science 2013) and head-and-neck squamous cell carcinoma, our goal is to elucidate the fundamental rules by which Tregs function in the context of cancer.  In essence, we aim to understand the “life cycle” of a tumor-infiltrating Treg, starting from its development in the thymus or periphery, its circulation throughout the body, its activation and recruitment into a developing neoplasm, and the functional role that the cell plays in shaping tumor development and metastasis.

2.  Aire and the establishment of immune tolerance

The promiscuous expression of tissue-restricted antigens in the thymus, driven in part by Autoimmune Regulator (Aire), is essential for the protection of peripheral tissues from autoimmune attack.  Aire-dependent processes are thought to promote both clonal deletion and the development of Foxp3+ Treg cells (Malchow et al. Science 2013), suggesting that autoimmunity associated with Aire deficiency results from two failed tolerance mechanisms.  In recent work (Malchow et al. Immunity 2016), our examination of autoimmune lesions in Aire-/-mice revealed an unexpected third possibility.  We found that the predominant conventional T cell clones infiltrating target lesions express antigen receptors that are preferentially expressed by Foxp3+ Treg cells in Aire+/+mice.  Our results suggest that Aire enforces immune tolerance by ensuring that distinct autoreactive T cell specificities differentiate into the Treg cell lineage.  Dysregulation of this process results in the emergence of "T-rogues" - Treg-biased specificities that are mis-directed into the T conventional subset and "go rogue" in the absence of Aire.  Broadly, our results suggest that the primary role of promiscuous gene expression in the thymus is not to promote clonal deletion, but instead lies in ensuring that distinct autoreactive clones differentiate into Treg cells.

3.  ROLE OF DENDRITIC CELLS IN TREG CELL DEVELOPMENT AND FUNCTION

The recognition of self antigen is critical for many aspects of Treg cell biology, including development, homeostasis, anatomical distribution, and function.  However, little is known about the identity of the cell types that present self antigen for recognition by Treg cells.  The identity of the "dance partners" that interface with Treg cells at various anatomical sites is likely to reveal new insights into Treg cell biology and immune regulation.  In a recent study, we identified a pivotal role for dendritic cells (DCs) in coordinating the development and homeostasis of an archetypal population of Aire-dependent organ-specific Treg cells (Leventhal et al., Immunity 2016).  The thymic development of this Treg population required antigen presentation and co-stimulatory signals provided by DCs, implying that Aire-dependent antigen must be transferred from medullary thymic epithelial cells to DCs.  In the periphery, the activation and enrichment of organ-specific Treg cells in the organ-draining lymph nodes required CCR7-dependent migratory DCs.  Our results demonstrate that the development and peripheral regulation of organ-specific Treg cells are dependent on antigen presentation by DCs, implicating DCs as key mediators of organ-specific immune tolerance.