James Gardner, MD, PhD

Assistant Professor
Surgery
+1 415 514-7420
Research Description: 

The Gardner lab studies novel mechanisms of immune tolerance and their applications in autoimmunity, transplantation, and cancer immunology. In particular we focus on the biology and function of a unique population of dendritic cells expressing the Autoimmune Regulator (Aire) gene.

Previously the lab has shown that by using bacterial artificial chromosome (BAC) transgenesis we could exploit the Aire promoter to drive expression of disease-relevant antigens and transcriptional reporters in mice. Using these tools, we were able to alter thymic negative selection against disease-relevant antigens, but we were also able to identify novel populations of Aire-expressing cells outside the thymus in the secondary and tertiary lymphoid organs - which we called extra-Thymic Aire-expressing Cells (eTACs). We have since gone on to describe some of the fundamental biology and immunology of this population.

We have found that, as in the thymus, Aire in eTACs regulates the expression of an array of tissue-specific antigens, though the set of antigens may be distinct from those expressed in the thymus. Further, we were able to demonstrate that eTACs could form long-term interactions with cognate T cells, and that the result of those interactions was deletional tolerance.

We subsequently demonstrated that eTACs were hematopoietic in origin and members of the dendritic cell family, were highly potent inducers of self-tolerance resistant to both innate inflammatory stimuli and costimulation, and that antigen expression in eTACs was sufficient to prevent insulitis and autoimmune diabetes in a murine adoptive transfer model.

We are currently using multimodal approaches from single-cell RNA-sequencing to ATAC-Seq to novel transgenic tools to understand the biology and immunology of this unique population of cells with significant potential for clinical relevance. We are interested in the role of such tolergenic APCs in normal immune homeostasis, as well as in disease-relevant applications from transplantation to tumor immunity.

Primary Thematic Area: 
Immunology
Secondary Thematic Area: 
Cancer Biology & Cell Signaling
Research Summary: 
Tolerogenic Antigen-Presenting Cells in the Immune System
Featured Publications: 

Extrathymic Aire-expressing cells are a distinct bone marrow-derived population that induce functional inactivation of CD4? T cells.

Immunity

Gardner JM, Metzger TC, McMahon EJ, Au-Yeung BB, Krawisz AK, Lu W, Price JD, Johannes KP, Satpathy AT, Murphy KM, Tarbell KV, Weiss A, Anderson MS

Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo.

The Journal of experimental medicine

Yadav M, Louvet C, Davini D, Gardner JM, Martinez-Llordella M, Bailey-Bucktrout S, Anthony BA, Sverdrup FM, Head R, Kuster DJ, Ruminski P, Weiss D, Von Schack D, Bluestone JA

Deletional tolerance mediated by extrathymic Aire-expressing cells.

Science (New York, N.Y.)

Gardner JM, Devoss JJ, Friedman RS, Wong DJ, Tan YX, Zhou X, Johannes KP, Su MA, Chang HY, Krummel MF, Anderson MS

Lineage tracing and cell ablation identify a post-Aire-expressing thymic epithelial cell population.

Cell reports

Metzger TC, Khan IS, Gardner JM, Mouchess ML, Johannes KP, Krawisz AK, Skrzypczynska KM, Anderson MS