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01 Jul 2023

Unravelling the complexity and diversity of memory T cells

Using state-of-the-art techniques, researchers at the Peter Doherty Institute for Infection and Immunity (Doherty Institute) discovered unprecedented insights into the diversity and functional characteristics of memory T cells – a major milestone in the field of immunology.

Memory T cells are like soldiers of the immune system: they play a vital role in mounting rapid and effective immune responses against previously encountered infections. The majority of T cells reside and perform these functions in tissues, not in the blood where they've traditionally been associated. The study, published in the journal Immunity, focused on distinguishing between two subtypes of memory T cells: circulating memory T cells which migrate the body through the blood and lymphoid organs, and tissue-resident memory T cells which permanently reside in peripheral tissues, such as the gut, and are ready to rapidly provide local protective responses upon pathogen reencounter.

Until now, accurately identifying and understanding the characteristics of these cells across different tissues has been challenging. Using a machine-learning computational tool (InfinityFlow), the team analysed the expression of hundreds of surface proteins at the individual cell level of circulating and tissue-resident memory T cells across different tissues and under various infection conditions.

The University of Melbourne Dr Maximilien Evrard, ARC DECRA Research Fellow at the Doherty Institute and lead author of the study, said their analysis revealed previously unknown differences within these cells.

“It is really exciting because we found that circulating and tissue-resident memory T cells each have distinct markers. This discovery allows us, for the first time, to accurately identify and study these cell populations,” said Dr Evrard.

"Unexpectedly, our study discovered that while tissue-resident memory T cells vary across different organs, their characteristics within the same organ are strikingly similar, regardless of the type of infections that generated them. This highlights that these cells don't follow a 'one-size-fits-all' pattern. Instead, their individual traits are largely shaped by the environment of the specific tissue they inhabit, rather than the type of infection they're responding to.

“Distinguishing memory T cell lineages is crucial for understanding the roles and behaviours of these cell populations in immune responses, particularly in the context of infections. By being able to identify and characterise them, we can gain insights into their specific functions, interactions and potential therapeutic targets.”

By determining the protein profiles for each subset of memory T cell, the team was able to demonstrate the effectiveness of strategies aimed at selectively removing either circulating or tissue-resident memory T cells from specific tissues.

The University of Melbourne Professor Laura Mackay, Laboratory Head at the Doherty Institute and senior author of the paper, said these findings deepen our understanding of how our immune system functions.

“The discoveries made in this research represent a real step forward for the study of immunology. By harnessing the power of machine-learning, we have uncovered valuable insights into memory T cell biology and opened pathways to improve immune-based therapies,” said Professor Mackay.

This research was done in collaboration with the Fred Hutchinson Cancer Research Center (USA), Sir Peter MacCallum Department of Oncology at The University of Melbourne, the Peter MacCallum Cancer Centre and the Agency for Science, Technology and Research (A*STAR) (Singapore).

Image caption: Memory CD8+ T cells provide protection against microbial and cancerous threats and can be divided into circulating and tissue-resident memory T cells based on their migratory properties. The illustration shows CD8+ T cells, depicted as grey suitcases, circulating on an infinity-shaped conveyor belt. Upon exit from the conveyor belt, CD8+ T cells (suitcases) change colour as they go through portals corresponding to distinct organs (skin, liver, gut, kidney) – this symbolises their differentiation into tissue-resident memory T cells triggered by signals from the local microenvironment. At the centre, an astronaut examines the phenotypic profile of tissue-resident memory T cells across tissue locations via a control panel (InfinityFlow), representing our web-based interface from which our datasets can browsed.  Credit: Kate Patterson

Peer review: Immunity

Funding: This research was funded by a Howard Hughes Medical Institute and Bill and Melinda Gates Foundation International Research Scholarship, the Australian Research Council (ARC), the Sylvia and Charles Viertel Charitable Foundation and the National Health Medical Research Council (NHMRC).