Role of ẞ2 integrin receptors for leukocyte functions in health and disease

1 PhD project offered in the IPP summer call 2021

This project is part of the Science of Healthy Ageing Research Programme (SHARP).

Scientific background

ß2 integrins consist of a variable α (CD11a-d) and CD18 as the constitutive ß subunit. ß2 integrins are expressed specifically in leukocytes, and are essential for their activation/polarization and effector functions, cell-cell interaction and migration. In human, hereditary loss-of-function mutations of CD18 result in LAD (leukocyte adhesion deficiency). LAD1 patients suffer from severe, reoccurring infections as well as from autoimmune diseases. Our lab has previously shown that CD18-/- mice serve as a suitable model to study the role of ß2 integrins for the functions of leukocytes. CD18-/- mice lack T cells in skin due to the importance of ß2 integrins for their migration. CD18-/- mice develop a psoriasis-like phenotype in an age-dependent manner, which emphasizes the role of skin-resident T cells to maintain tissue homeostasis. Above, in light of the general importance of ß2 integrins for T cell functions, it is conceivable that dysregulation of ß2 integrin activity may contribute to T cell immunosenescence.

PhD project: Role of skin-resident lymphocytes for tissue homeostasis and peripheral tolerance in ageing skin

This project aims to delineate the overall requirement of skin-resident T cells for tissue homeostasis and of ß2 integrins for T cell immunosenescence by in-depth transcriptome analysis of keratinocytes/fibroblasts and (skin-resident) CD4+ T cells in young versus old wild type and CD18-/- mice. Similarly, Rag2-deficient mice (Rag2-/-) that lack T and B cells altogether, are also deficient of skin-resident T cells, thus serving as a second experimental system. Besides transcriptome analysis, derived cell populations will be analysed by multicolor flow cytometric analysis (up to 30 markers in parallel) to delineate the composition and activation state of leukocyte populations, with a focus on T cells. Flow cytometric analysis will also serve to validate differential expression of interesting candidate genes identified by transcriptome analysis. To pursue this project stat-of-the-art techniques and equipment will be employed.

If you are interested in this project, please select Stephan Grabbe as your group preference in the IPP application platform.

Publications relevant to the project

Bednarczyk M, Stege H, Grabbe S, Bros M (2020) β2 Integrins-Multi-Functional Leukocyte Receptors in Health and Disease. Int J Mol Sci, 21(4):1402 Link

Balkow S, Heinz S, Schmidbauer P, Kolanus W, Holzmann B, Grabbe S, Laschinger M (2010) LFA-1 activity state on dendritic cells regulates contact duration with T cells and promotes T-cell priming. Blood, 116(11):1885-94 Link

Scharffetter-Kochanek K, Lu H, Norman K, van Nood N, Munoz F, Grabbe S, McArthur M, Lorenzo I, Kaplan S, Ley K, Smith CW, Montgomery CA, Rich S, Beaudet AL (1998) Spontaneous skin ulceration and defective T cell function in CD18 null mice. J Exp Med, 188(1):119-31 Link

Barbé-Tuana F, Funchal G, Schmitz CRR, Maurmann RM, Bauer ME (2020) The interplay between immunosenescence and age-related diseases. Semin Immunopathol, 42(5):545-557 Link

 

Contact

Prof. Stephan Grabbe (If you are interested in this project, please select Stephan Grabbe as your group preference in the IPP application platform.)

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Dr Emil Karaulanov

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