Friends or foes? Resident T cells in the skin

8 February 2019

The skin is the largest organ in the human body and functions as a shield against external insults such as infections or injury – and as vital protection for our internal organs.

To provide effective protection, the skin is equipped with immune cells from both the innate and adaptive immune systems, ready to fight traditional pathogens. However, its in-built immune system faces other threats related to modern living, such as allergens and pollutants in the environment, stress at home and work, and unhealthy dietary habits, among others.

Extensive research has been carried out in past decades on the skin’s role in the immune system and cutting-edge technologies deployed to seek treatment for skin ailments, for example, lymphoma, and autoimmune diseases such as psoriasis and vitiligo.

One field garnering particular attention involves T cells, a type of white blood cell developed in the thymus, and a subtype of T cells called tissue-resident memory T cells for their potential role in tumour immunotherapy and autoimmune diseases.

Among the young researchers immersed in this area of exploration is Dr Stanley Cheuk (Croucher Scholarship 2011), who studied the role of resident memory T cells in psoriasis and vitiligo while training in skin immunology at Karolinska Institutet, Stockholm, Sweden.

T cells are an integral part of the adaptive immune system. They are a type of lymphocyte bearing a T cell receptor that can recognise foreign antigens in infected cells or aberrant cells such as tumour cells.

Tens of billions of T cells circulate in the blood and lymphatic system detecting foreign antigens. Whenever there is skin infection, these cells are recruited to fight, and in the process a sub-population of T cells remains in the tissue. Cells that occupy tissues without circulating are known as tissue-resident memory T cells (TRM cells).

Psoriasis and Vitiligo

During his PhD, Cheuk studied the heterogeneity of skin resident T cells and their clinical implications in skin autoimmune diseases.

Psoriasis is a chronic inflammatory skin disease, characterised by thickening of the epidermis (the outer layer of the skin) and massive infiltration of immune cells in the skin. One long-established observation is that this chronic inflammatory disease tends to return in the area previously affected.

Cheuk and his PhD supervisor, Dr Liv Eidsmo, hypothesised that a population of resident memory T cells resides in the same area as that of the old skin lesion and, through reactivation, triggers the recurrent response in the same area of the skin. They found that this involves the production of interleukin 17 (IL-17), a cytokine that leads to inflammation.

“IL-17 mediated inflammation also further recruits T cells and other immune cells into the skin and releases a downstream inflammatory cascade,” Cheuk explained.

The research involved characterising the phenotype and function of skin resident T cells using multicolour flow cytometry and determining the transcriptional profiles of the T cells, sorted from human skin biopsies, as analysed by RNA-sequencing.

In vitiligo, a chronic autoimmune depigmentation skin disorder resulting from the loss of melanocytes, Cheuk and his colleagues found that resident memory T cells expressing CD49a, a protein that allows adhesion to skin collagen, are highly enriched in the depigmented skin of vitiligo patients.

These CD49a+ T cells are poised for cytotoxic function. In the context of infection and tumour, they would be effective in killing infected or malignant cells. However, in the case of vitiligo, they mistakenly recognise melanocyte antigens. Their high cytotoxic nature most likely results in the destruction of melanocytes and leads to skin depigmentation in vitiligo patients.

In light of this finding, Cheuk compared pathogenic resident T cells in psoriasis and vitiligo, and found that resident memory T cells that do not express CD49a preferentially produce the pathogenic cytokine of IL-17. The CD49a marker therefore distinguishes two functionally distinct subtypes of tissue resident T cells in human skin.

“During my time at Karolinska, I developed a deep interest in the function and possible medical application of T cells. In my postdoctoral training, I would like to further develop my knowledge and research skills in studying how these cells are formed in the first place,” said Cheuk.

22q11.2 Deletion Syndrome

Previously known as DiGeorge syndrome, 22q11.2 deletion syndrome is a developmental disorder where there is a partial loss of the chromosome 22 in human patients. The condition is characterised by symptoms including congenital heart problems, abnormal facial and cranial structure, cleft palate and learning disabilities.

The thymus development of these patients is also affected, resulting in either a complete loss of thymus or a smaller one compared with healthy individuals.

To date, there are limited treatment options for patients with the thymus anomalies of this syndrome, and it remains under-researched, partly because cardiac and endocrinal symptoms often require more immediate attention. Given the central role of the thymus in T cell development, many of the patients with 22q11.2 deletion syndrome also manifest various degrees of immunodeficiency and autoimmunity.

In 2018, Cheuk joined Prof Georg Hollander’s group at the University of Oxford as a visiting research fellow and is now embarking on the research in early thymic development and immunodeficiency associated 22q11.2 deletion syndrome.

Cheuk explained the research that could lead to reversal or prevention of this thymic developmental abnormality and therefore help patients regenerate a healthy immune system. “We are developing an experimental model to mimic the diseases by targeting the important genes in 22q11.2 deletion in order to understand the molecular mechanism behind the thymus developmental defects and to probe treatment options.”

Power of Persistence

Despite the rapid advancement in biomedical sciences, scientists often encounter more failures than successes. It takes years for scientific research to materialise and requires extensive collaboration to achieve outcomes that can be applied in medicine.

Many young researchers work under such pressure, but Cheuk says that learning from failure is the way to success.

“We need to learn from our failure in experiments, improve, and avoid repeating mistakes. There is no failure in the true sense. Scientific experiments are sometimes frustrating but each one of us has to learn how to deal with it,” he said.

“My view on this is that it is an opportunity to learn new things, and should be taken as ultimate motivation to improve our research.”

Dr Stanley Cheuk is a visiting research fellow in the Department of Paediatrics at the University of Oxford. He obtained his MSc in biomedicine and PhD in immunology from Karolinska Institutet, Sweden, in 2011 and 2016 respectively. He was awarded the Croucher Scholarship in 2011 for his doctoral study for his study at the Karolinska Institutet in Stockholm Sweden on the topic of resident memory T cells in the human skin under the supervision of Dr Liv Eidsmo and Prof. Mona Ståhle. His PhD works revealed pathogenic resident memory T cells in resolved psoriasis skin that express IL-17 upon activation and uncovered the functional heterogeneity of resident T cells in human skin and their clinical implication in skin autoimmune diseases, such as psoriasis and vitiligo. After finishing his PhD study, Dr Cheuk went on to pursue a postdoctoral research training in the Oslo university hospital where he studied T cell-based tumour immunotherapy.

To view Dr Cheuk’s Croucher profile, please click here