Steroid control of cell fates & phenotypes

We are interested in how individuals adaptively regulate immune development and immune responses, especially in response to environmental stressors. Our work aims to understand how steroids – at the level of single cells, tissues, organisms, and species – operate as master controllers of developmental trajectories and complex immune phenotypes. We also pursue strategies targeting these signals with the goal of preventing and treating diseases.

Tissue and cell-specific steroid signaling

Glucocorticoids from the adrenals and sex steroids from reproductive tissues circulate throughout the body, diffusing through tissues to coordinate systemic responses. However, certain tissues, including the thymus, can independently synthesize their own glucocorticoids. Thymic epithelial cell-synthesized glucocorticoids signaling developing T cells and are necessary for generation of a competent adaptive immune system.

We are exploring how paracrine glucocorticoid signaling occurs in the thymus and other immune tissues. Rather than widespread diffusion, thymus glucocorticoids may be targeted to particular T cells in the thymus, a novel mechanism of steroid signaling.

Local steroid production differs across contexts. In the thymus, medullary epithelial cells independently synthesize glucocorticoids, and these appear to be delivered to a specific subset of developing T cells. This suggests that glucocorticoids can act as cell-targeted signals. In tumors, cancer cells amplify blood-borne glucocorticoids to create an immunosuppressive microenvironment, preventing CD8+ T cells from killing cancer cells.

We are exploring how local steroids promote or inhibit immune responses, and how these can be specifically targeted to regulate immunity in pathological conditions.

Steroid control of immune cell development & differentiation

T cells recognize pathogens or cancer cells via their T cell antigen receptor (TCR). Each T cell expresses a unique TCR, and a huge diversity of TCRs on different T cells allows recognition of almost any antigen. This diversity is generated by random recombination of TCR genes during T cell development in the thymus. T cells with nonfunctional TCRs are eliminated (as these aren’t useful), as are T cells with strongly self-reactive TCRs which might cause immunity (negative selection). Only T cells with moderately signaling TCRs become part of the mature immune system. Steroids are immunosuppressive and can kill T cells, but also antagonize TCR signaling in the thymus to allow survival of T cells that would otherwise be negatively selected. In this way, steroids strengthen the TCR repertoire.

We study how steroid production in the thymus and steroids from the circulation control TCR signaling decisions that lead to cell death or survival, and how environmental stressors shift selection, potentially predisposing to immunodeficiency or autoimmunity.

Tumors have multiple ways of evading immune responses, in particular producing molecules to suppress cancer-killing T cells. We have found that multiple tumor types amplify circulating glucocorticoids to create a potently immunosuppressive environment. In addition to suppressing the activity of killer T cells, these also activate regulatory T cells, which function as potent suppressors of immunity.

We are investigating how steroids control regulatory T cell phenotypes, and how they act within the tumor to potentiate their immunosuppressive actions. We are also studying how tumor-specific or immune cell-specific ablation of steroid production alters killer and regulatory T cell phenotypes, and reduces tumor progression. In combination with immunotherapy, inhibition of glucocorticoid production appears to additionally help control tumor progression.

New tools to detect & quantify cell-specific steroid signaling

Steroid receptors and other nuclear receptors are ligand-dependent transcription factors: their activity is rapidly turned on and off by ligand presence/absence. Nuclear receptors drive cell development, differentiation, and death, and are important in various diseases. However, current techniques cannot quantify a cell’s ligand exposure. We have developed a technique to use endogenous receptors as biosensors, for the first time identifying and quantifying steroid signaling within single cells.

We are using this technique to detect steroid signaling circuits within immune and tumor tissues. We are also developing genetically-encoded fluorescent sensors to explore steroid signaling dynamics in live cells.