Composition and maintenance of skin resident T-cells in health and disease

Tissue-resident memory T cells (TRM) reside in healthy skin at sites of previous infections. Upon re-infection, TRM cells rapidly respond by initiating tissue inflammation and exert effector functions to eliminate pathogens. TRM cells are potent effector cells and as such, they are key players in focal inflammatory skin diseases. This doctoral thesis investigates effects of aging, tissue microenvironment, and inflammatory skin diseases on the composition of human TRM cells by analyzing patient material with technologies including single cell sequencing with T cell receptor sequencing and mechanistic experiments. The aim was to elucidate the composition and mechanisms for long-term maintenance of the TRM cell population in the skin.

PAPER I showed that the number of TRM cells, in particular epidermal cytotoxic CD103+CD49a+ TRM cells increased with age in human skin and maintained functionality and diversity in the skin of the elderly.

PAPER II investigated the T cell composition in never-lesional skin of psoriasis patients (NLP) compared to healthy skin. NLP showed higher frequencies of IL-17 and IFN-g producing CCR6+ T cells and CD103+CD49a- TRM cells compared to healthy skin. CCL20, the ligand for CCR6, was upregulated in the epidermis of NLP at baseline, indicating tissue wide pro-inflammatory changes in the microenvironment poised towards disease development.

PAPER III analyzed T cell composition in joint and skin in patients living with psoriasis arthritis. Only discreet T cell clonal overlap was detected between these two anatomically distinct and the few shared clones showed different phenotypes in different sites, indicating tissue microenvironment specific adaption of T cells.

PAPER IV To address the origin or TRM cells in adult human skin, clonal overlap between circulating T cell populations and skin TRM cell populations was assessed. Central memory T cells (TCM) were superior in giving rise to CD103+CD49a+TRM-like cells. RUNX3 and RUNX2 regulated CD49a expression and TRM cell differentiation. The study suggests that TCM could serve as a circulating precursor for cytotoxic CD103+CD49a+ TRM cells.

PAPER V explored the possibility of local TRM precursor cells in humans to replenish the pool of skin TRM cells. A small population of CD69+CD62L+ CD103-CD49a- TRM cells enriched in genes related to multipotency and lower differentiated was found in skin and showed clonal overlap with CD103+CD49a+TRM cells. CD69+CD62L+ TRM cells excelled in proliferation and developed into CD103+CD49a+ TRM-like cells that acquired functional similarities to bona fide TRM cells following stimulation. This indicates that CD69+CD62L+ TRM can act as a local precursor to replenish the pool of skin TRM cells.

In conclusion, TRM compositions are altered during healthy ageing (PAPER I) and in different psoriasis- affected microenvironments (PAPER II and III). Human skin TRM cells can be maintained through two mechanisms local and systemic. Circulatory counterparts potentially can provide immunity to distant body sites (PAPER IV and V).

List of scientific papers

I. Skin T cells maintain their diversity and functionality in the elderly. Hanako Koguchi-Yoshioka , Elena Hoffer, Stanley Cheuk, Yutaka Matsumura, Sa Vo, Petra Kjellman, Lucian Grema, Yosuke Ishitsuka, Yoshiyuki Nakamura, Naoko Okiyama, Yasuhiro Fujisawa, Manabu Fujimoto M, Liv Eidsmo, Rachael A Clark, Rei Watanabe. Communications biology. 2021, Vol 4, Page 1-8.
https://doi.org/10.1038/s42003-020-01551-7

II. A skewed pool of resident T cells triggers psoriasis-associated tissue responses in never-lesional skin from patients with psoriasis. Irene Gallais Serezal, Elena Hoffer, Borislav Ignatov, Beatrice Zitti, Marucs Ehrström, Liv Eidsmo. The Journal of Allergy and Clinical Immunology. 2019, Vol 143, Pages 1444- 1454.
https://doi.org/10.1016/j.jaci.2018.08.048

III. Clonal overlap of pathogenic IL-17-Producing T cell clones in psoriasis lesions and joints of psoriatic arthritis patients. Wenning Zheng*, Elena Hoffer*, Daniel Sortebech, Martin Skeppsholm, Josefin Lysell** and Liv Eidsmo**. *Co-first author. **Co-senior authors. [Manuscript]

IV. Human skin-resident CD8+ T cells require RUNX2 and RUNX3 for induction of cytotoxicity and expression of the integrin CD49a. Beatrice Zitti,* Elena Hoffer*, Wenning Zheng, Ram Vinay Pandey, Heinrich Schlums, Giovanna Perinetti Casoni, Irene Fusi, Lien Nguyen, Jaanika Kärner, Efthymia Kokkinou, Anna Carrasco, Jessica Gahm, Marcus Ehrström, Staffan Happaniemi, Åsa V Keita, Carlotte RH Hedin, Jenny Mjösberg, Liv Eidsmo**, Yenan T Bryceson**. Immunity. 2023, Vol 56, Page 1285-1302. *Co-first author. **Co-senior authors.
https://doi.org/10.1016/j.immuni.2023.05.003

V. Epidermal CD69+CD62L+ TRM, a subset with renewal capacity gives rise to CD103+CD49a+ TRM- like cells. Elena Hoffer*, Wenning Zheng*, Beatrice Zitti, Danie Sortebech, Rasmus Agerholm-Nielsen, Chenming Zhang, Trine Schønfeldt, Tilen Trselic, Sofia Papavasileiou, Jaanika Kärner, Marcus Ehrström, Jessica Gahm, Jenny Mjösberg, Josefin Lysell, Niels Odum, YenanT Bryceson, Patrick Brunner, Carmen Gerlach, Liv Eidsmo. *Co-first author. [Manuscript]