Research interests

We are interested in the following areas of immunology and the translation of our research into clinical benefit of patients:

1. Antigen presentation

Before immunity is stimulated, the degradation of an antigen (e.g. a viral/bacterial/tumour protein) into fragments (peptides) in antigen presenting cells (e.g. dendritic cells) is necessary. These peptides are then processed in two pathways:

I. If they end of in the cell cytoplasm, the peptides enter the MHC class I pathway, where the signals produced by the antigenic peptides prime killer T cells to destroy the viral/bacterial-infected, or tumorous, cells.

II. Peptides which end up in the lysosome/endosome compartments are processed via the MHC class II pathway, where they send signals to prime helper T cells. The role of helper T cells is to maintain and help the antibody producing cells: Killer T cells and B cells.

We have demonstrated that during antigen presentation, a pool of overlapping peptides enters both the MHC class I and class II pathways. Overlapping peptides are therefore able to simultaneously recruit both helper T cells and killer T cells, whereas a soluble protein preferentially enters the MHC class II pathway to stimulate helper T cells.

The application of this discovery – overlapping peptides as prophylactic and therapeutic vaccines against infectious diseases and tumours, is a novel vaccine design strategy which will maximally expand both killer and helper function of immunity. Overlapping peptides can be made by the solid-phase chemistry method. Moreover, to reduce the cost of production, we have successfully made overlapping peptides by recombinant method which is at least a thousand time's cheaper than the solid-phase method.

References:

2. Immune homeostasis

The main function of the immune system is to check for “invaders” such as microorganisms and tumours. However, the immune system must be tolerant to self-antigens, in order to protect against inappropriate immune responses on one’s own cells and tissues. This balance of immune functions is called immune homeostasis.

Aberrations of immune homeostasis results in immunological pathogenesis: whilst an overactive immune system causes autoimmune diseases and allergies, the suppression or deficiency of immunity may lead to cancers.

Tumour necrosis factor alpha (TNF-α) is a cytokine crucial in maintaining immune homeostasis. Not only does it stimulate the proliferation of lymph cells in response to “invaders”, it is also responsible for killing antigen-activated lymph cells.

How can one cytokine promote both cell proliferation and cell death? We are currently working to understand the mechanisms of TNF- α related apoptosis and necrosis, leading to its clinical application in inflammatory and autoimmune diseases and cancer treatments. A manuscript from this work is in preparation and submission.

In another study, we worked with regulatory T cells (Treg), which function to maintain immune homeostasis. Treg cells are found to be over-suppressed in the immune system of cancer patients. We have shown the depletion of Treg, in addition to the stimulation of natural killer T (NKT) cells in cancer models, increase tumour survival rate from 44% to 85%. We hope these findings will aid the development of a novel immunotherapy for cancer treatment.

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Reference:

3. TNF fragments related functions

TNF is a protein evolved from 550 million years ago. There are several conserved sequences in TNF. Their functions are unknown. We have revealed that these sequences are related to cell death, either apoptosis or necrosis.

By investigation of the conserved sequences in TNF and their interactions with body's immune system, we have discovered a new biomarker. When the biomarker binds to TNF, it turns the TNF-related apoptosis into necroptosis; the minimum inflammatory response (apoptosis) develops into a strong inflammatory pathogenesis (necroptosis). We therefore named the biomarker as inflammation enhancer (IE). Together with TNF, IE induces necroptosis in endothelial cells and chondrocytes; increases permeability of blood vessels. We intend to further characterise IE and to establish its relationship with acute and chronic inflammatory diseases. The result of this study will be useful for development of diagnostics and therapeutics for acute and chronic inflammatory diseases.

Reference:

Evolutionarily conserved primary TNF sequences relate to its primitive functions in cell death induction

Wenshu Lu, Qiongyu Chen, Songmin Ying, Xiaobing Xia, Zhanru Yu, Yuan Lui, George Tranter, Boquan Jin, Chaojun Song, Leonard W. Seymour, Shisong Jiang

Journal of Cell Science (2016)129 (1), 108-120