Description of Research Expertise

Research interests:
Mast cell signaling in allergy; effect of mast cells on T cell responses; regulatory T cell expansion and homeostasis; Natural killer (NK) cell education and signaling

Keywords:
Mast cells, CD8+ T cells, CD4+ T cells, Regulatory T cells, NK cells, Signal Transduction, Cellular Immunology, Antigen Presentation

Research summary:
1) Mast cell signaling in allergy
Mast cells belong to the innate immune system and are mainly regarded as the key player in allergic responses owing to their ability to immediately release inflammatory mediators upon IgE receptor (FcεRI) crosslinking by IgE/allergens. The importance of mast cells in allergy is evidenced by the lack of cutaneous and systemic allergic responses in mice that lack mast cells. My laboratory is interested in how signals downstream of FcεRI lead to inflammatory mediator release by mast cells, in hopes of identifying new therapeutic targets to counteract allergic disease.

2) The role of mast cells in T cell activation
Although mast cells are most well known for their involvement in allergy, the importance of mast cells extends far beyond allergic disease. For example, mast cells contribute to protection against parasites, to the development of hypersensitivity disorders, and to the induction of several autoimmune diseases. T cells play a vital role in these diseases, suggesting that mast cells may influence T cell activation. One mode by which mast cells activate T cells may be through their involvement in antigen presentation. To investigate this, we examined the ability of mast cells to activate T cells after incorporation of antigen through IgE/FcεRI. Through these studies, we found that IgE crosslinking results in mast cells apoptosis, which then become a source of antigen to be presented to T cells by dendritic cells. Thus, mast cells appear to be indirectly involved in antigen presentation by acting as an antigen-concentrating depot. We have also found that mast cells can express MHC class II under certain circumstances and directly present antigens to T cells in a tolerogenic manner. We are continuing to investigate how these two modes of involvement in antigen presentation (direct and indirect) by mast cells contribute to immune responses in a variety of disease models.

3) Regulatory T cell expansion and homeostasis
Regulatory T cells represent a subset of CD4+ T cells that possess the ability to suppress the activation and expansion of other conventional CD4+ T cells. They are distinguished from conventional T cells by constitutive expression of CD25 and the transcription factor Foxp3. The importance of regulatory T cells is evidenced by the severe autoimmunity that develops in mice and humans lacking regulatory T cells. We have recently found that a subset of dendritic cells possess the ability to expand regulatory T cells, which drastically increases their potential to suppress conventional CD4+ T cell expansion. We are continuing to investigate what makes these dendritic cells preferentially expand regulatory T cells and to examine the role that these dendritic cells play in the homeostasis of regulatory T cells as well as in the prevention of autoimmune diseases such as multiple sclerosis, diabetes, and inflammatory bowel disease.

4) NK cell education and signaling
NK cells are innate immune cells that provide a critical line of defense against intracellular pathogens and tumors by displaying cytotoxicity and producing immune-activating cytokines. One key mechanism that regulates their activation involves the expression of activating receptors that are finely counterbalanced by inhibitory MHC class I-binding receptors. Thus, the interaction of NK cells with abnormal cells that have decreased MHC class I expression relieves the inhibition conferred by the MHC-binding inhibitory receptors, leading to activation and cytotoxicity by the NK cell. NK cells heterogeneously express one or more of the many inhibitory receptors, which are acquired by NK cells during later stages of their development. The heterogeneity of NK cell receptor expression allows NK cells to discriminate between cells expressing normal and abnormal amounts of various MHC class I molecules. As the signaling requirements of these receptors during development and effector function remain unclear, we have been investigating the signal transduction pathways during NK cell activation. In doing so, we have identified some key signaling molecules that are necessary for proper acquisition of MHC-binding inhibitory receptors during development. We are further investigating the molecular mechanisms that are responsible for regulating inhibitory receptor acquisition during NK cell development and how it relates to the functional outcome of the NK cell response.

Rotation Projects are available in all areas

Lab personnel:
Rebecca May, Graduate Student
Priti Ojha, Research Specialist
Mariko Okumura, Research Specialist
Norifumi Sawamukai, Postdoctoral Fellow
Tao Zou, Graduate Student