The role of tissue-resident memory T cells in barrier immunity, cancer and autoimmune diseases
Infections are commonly acquired through barrier tissues such as the skin, gut and lung, hence establishing memory CD8⁺ killer T cell populations at these sites is critical for effective immune protection. Likewise, an effective local memory CD8⁺ T cell response is critical to cancer immunosurveillance, preventing the development and spread of solid tumours. While most memory T cells circulate in the blood, a distinct lineage, termed tissue-resident memory T (TRM) cells, resides and remains in peripheral tissues. Our group has shown that these cells form a defensive barrier providing immediate local control of viral infection and cancer recurrence. Our current research focuses on developing novel strategies to boost TRM cell responses, and therefore exploit these cells in settings such as vaccination and cancer immunotherapy. Work in our laboratory also aims to understand the role of TRM cells in autoimmune conditions such as psoriasis and alopecia areata and investigate new approaches to eliminate pathological cells from peripheral tissues.
Understanding the fate decisions that govern memory T cell development
An effective immunological memory response is required for protection against disease throughout an individual’s lifetime. Following exposure to antigen, naïve T cells expand and differentiate to resolve an infection, after which memory T cells are formed to provide long-lasting protective immunity. The memory T cell pool can be partitioned into heterogeneous populations, each possessing different migratory and functional properties, and whose development relies on genetic regulators and environmental signals. Understanding these cell fate decisions provides an avenue to enhance immunological memory responses. Using various infection and tumour models, our group is investigating the regulatory cues and mechanisms that govern memory T cell development in different tissues, with a focus on the transcriptional networks that regulate commitment to various memory T cell lineages.
Identifying the mechanisms of immune cell development in peripheral tissues
It is now clear that various immune cell populations including T cells, innate lymphoid cells and NKT cells can establish tissue residency and persist long-term in peripheral tissues. Our group is interested in the role of the tissue microenvironment in shaping these immune cell populations and are studying the tissue-tropic factors and microbial signals that govern the environmental adaptation of immune cells to different tissues. We are also investigating the effect of commensalism and microbial experience on immune cell populations and tissue homeostasis. Our goal is to decipher the molecular framework for tissue-resident lymphocyte differentiation, which will provide a basis for targeting these cells in future immune cell-based therapies.
Whole body analysis of human T cell development and function
The majority of T cell responses occur in tissues; however, current knowledge of human T cells is largely derived from blood. In collaboration with the Australian Donation and Transplantation BioBank (ADTB), our group studies the T cell landscape in multiple lymphoid, visceral and barrier sites from research-consented organ donors. We seek to investigate immune cell distribution across the body and understand the pathways that guide T cell differentiation and maintenance in diverse tissue sites. Our work aims to better-inform the development of immunotherapies that modulate tissue-based cellular responses.
Professor Laura Mackay is a Laboratory Head and Immunology Theme Leader at The Doherty Institute. Laura is a Howard Hughes Medical Institute (HHMI) and Bill & Melinda Gates International Scholar, a Dame Kate Campbell Fellow, a Sylvia & Charles Viertel Charitable Foundation Senior Medical Research Fellow, a National Health and Medical Research Council (NHMRC) Leadership Fellow, and in 2022 was the youngest ever Fellow elected to the Australian Academy of Health and Medical Sciences. Laura obtained her PhD from The University of Birmingham, U.K. in 2009, before commencing a post-doctoral position with Professor Francis Carbone at The University of Melbourne. In 2016, she established an independent group at The Doherty Institute.