Forum for Nordic Dermato-Venereology Nr 4, 2019 | Page 20

Dissertation
Elisa Martini – Compartmentalisation of the Immune Response in Human Skin
Compartmentalisation of the Immune Response in Human Skin: Cross-talk
between Dendritic Cells and T Cells in Healthy Conditions and in Psoriasis
E lisa M artini
Department of Medicine, Division of Dermatology and Venereology, Karolinska University, Solna, Sweden. E-mail: elisa.
[e-mail]
Elisa Martini defended her thesis in Karolinska University Hospital, Solna on May 4, 2018. Opponent was
Clare Bennett, Department of Hematology, University College London, UK. Principal supervisor was Associate
Professor Liv Eidsmo, and co-supervisors were Anna Smed Sörensen, Professor Mona Ståhle, Department of
Medicine, Karolinska Insitutet, Solna and Professor Francis R. Carbone, Department of Microbiology and Im-
munology, University of Melbourne, Australia. The thesis is available here: https://openarchive.ki.se/xmlui/
handle/10616/46267
The skin is a highly compartmentalised barrier in which
epidermis and dermis form distinct microanatomical niches.
These two skin niches host different subsets of dendritic cells
(DCs) and T cells, immune cells that form the first line of an-
timicrobial defence. In psoriasis, an inflammatory skin disease
associated with overexpression of IL-17, both DCs and T cells
are altered. The thesis “Compartmentalisation of the immune
response in human skin: cross-talk between dendritic cells
and T cells in healthy conditions and in psoriasis” explores
compartmentalised differences in DCs and T cells functional-
ity in different phases of psoriasis compared to healthy skin.
My analysis focused on inflammatory mediators or cytokines
that were produced by DCs and T cells in homeostasis and
inflammation. Moreover, after defining the cytokines present
in the skin environment in psoriasis, we investigated how
these cytokines affected the development and function of T
cells residing in the skin.
In study I we observed that the total number of DCs in the
epidermis in active psoriasis dramatically increased compared
to healthy skin, due to the infiltration of a population of
inflammatory DCs. These cells displayed high expression of
pro-inflammatory genes and were capable of producing the
disease-driving cytokine IL-23 after stimulation. In accordance
with other studies, the number of DCs normalised in the epi-
dermis of resolved psoriatic skin after successful treatment, but
the remaining cells retained high expression of pro-inflamma-
tory genes and were poised to produce IL-23, indicating that
epidermal DCs may activate T cells in resolved psoriatic skin.
duced by epidermal T cells from active psoriasis. Taken that
perforin was not expressed, we next tested pro-inflammatory
features of Granzyme A. Primary human keratinocytes were
stimulated with Granzyme A in combination with the pso-
riasis-associated cytokine IL-17. Granzyme A together with
IL-17 activated keratinocytes to release mediators involved in
inducing inflammation and attracting other immune cells into
the skin. This study revealed a new pathway of T cell-mediated
recruitment of immune cells in psoriasis.
Study III focused on the dermal compartment in resolved
psoriasis. Here we identified an enrichment in the expression
of the tolerogenic markers FOXP3, CTLA4, PD1 (T cells), and
IDO (DCs). DCs from the dermis of resolved skin were also
characterised by their enhanced ability to produce the anti-in-
flammatory molecule IL-10. Analysis conducted by confocal
microscopy revealed the presence of clusters of Foxp3+ regu-
latory T cells in close proximity to DCs, indicating a possible
interaction between regulatory T cells and DCs in resolved
skin to maintain a tolerogenic state within the dermis, de-
spite the constant presence of IL-17-producing T cells and
IL-23-producing DCs.
epidermal skin T cells did not change their phenotype after the
exposure to the same conditions. However, when epidermal
skin T cells were stimulated with pro-inflammatory cytokines,
their functionality was affected despite maintained expression
of CD69, CD103 and CD49a, which indicates functional
plasticity in these cells.
In conclusion, the results from my PhD project provided an
insight in the distinct inflammatory potential of DCs and
T cells located in different skin compartments in different
phases of psoriasis. Moreover, I showed that the phenotype
and functionality of skin T cells is affected by their surround-
ing environment. Collectively, the results indicated that the
compartmental differences of immune cells residing in the two
skin layers should be taken into consideration when designing
targeted therapies.
L ist
I.
II.
Study IV focused on the phenotypic and functional plasticity
of skin T cells. The Eidsmo laboratory previously showed that
skin T cells in homeostasis are divided in distinct functional
subsets based on their expression of the markers CD69, CD103
and CD49a. In this final study, we showed that skin T cells
residing in the dermis, mainly CD69 + CD103 – CD49 – , upregu-
lated CD103 or both CD103 and CD49a after stimulation with
cytokines present in the skin environment in homeostatic
conditions. In stark contrast with the dermal skin T cells, the
III.
IV.
V.
of publications
Martini E, Wikén M, Cheuk S, Gallais Zérézal I, Baharom F, Ståhle
M, et al. Dynamic changes in resident and infiltrating epidermal
dendritic cells in active and resolved psoriasis. J Invest Dermatol
2017; 137: 865–873.
Cheuk S, Martini E, Bergh K, Chang D, Rethi B, Ståhle M, et al.
Granzyme A potentiates chemokine production in IL-17 stimulated
keratinocytes. Exp Dermatol 2017; 26: 824–827.
Martini E, Cheuk S, Hoffer E, Wikén M, Gallais Sérézal I, Eidsmo L.
Anti-inflammatory features of T cells and dendritic cells residing in
the dermis of psoriasis-treated patients. In manuscript.
Martini E, Kärner J, Cheuk S, Detlofsson E, Bryceson Y, Eidsmo
L. Development and plasticity of human skin resident T cells. In
manuscript.
Eidsmo L, Martini E, Human Langerhans cells with pro-inflam-
matory features relocate within psoriasis lesions. Front Immunol
2018; 22: 300.
In study II we showed that Granzyme A, a cytotoxic protein
normally produced in combination with perforin, was pro-
Fig. 1. Elisa Martini during her presentation.
130
Fig. 2. Elisa Martini with the opponent Clare Bennett, Department of
Hematology, University College London, UK.
Forum for Nord Derm Ven 2019, Vol. 24, No. 4
Forum for Nord Derm Ven 2019, Vol. 24, No. 4
D issertation
131