PhD Projects on offer
How do killer cells contribute to reproductive success?
Supervisor: Francesco Colucci
Natural Killer (NK) cells are bone marrow-derived cytotoxic lymphocytes of the innate immune system [1]. Unlike their counterparts in blood, uterine NK (uNK) cells found at the maternal-fetal interface are only weakly cytolytic but they do secrete a wide range of angiogenic factors and cytokines that may influence placentation. Indeed, uNK cells are crucial in the development of a healthy materno-fetal nutritional supply line both in humans and mice [2, 3]. Research in our lab has recently shown that mouse uNK have a unique repertoire of cell surface receptors that bind possible target cells [4] and a unique repertoire is also observed in human uNK cells [5], suggesting that the mechanisms of cellular differentiation and selection of uNK cells are conserved in the two species. Fetal MHC molecules derived from paternal and maternal genes are the prime candidates the interactions between uNK cells and the fetal derived trophoblast. Genetic studies indicate that certain combinations of polymorphic NK receptors and fetal MHC molecules are associated with reproductive failure, including pre-eclampsia and recurrent miscarriage [6].
Our key question is: How do uNK cells recognise and respond to trophoblast and how does this affect trophoblast behavior resulting in reproductive success? The aim of this project is to define how uNK cells influence placental development. The project will be developed in collaboration with Ashley Moffett and Myriam Hemberger. You will be using advanced dissection techniques, transgenic mice, flow cytometry, histology, microscopy and gene expression analysis to test the hypothesis that there is a cooperative partnership between fetal antigens and the maternal immune system that leads to a successful pregnancy [7].
References:
1. Colucci F, Caligiuri MA, Di Santo JP (2003). What does
it take to make a natural killer? Nat Rev Immunol. 3:413-25.
2. Moffett A, Loke C (2006). Immunology of placentation in
eutherian mammals. Nat Rev Immunol. 6:584-94.
3. Croy BA, van den Heuvel MJ, Borzychowski AM, Tayade C
(2006). Uterine natural killer cells: a specialized differentiation regulated
by ovarian hormones. Immunol Rev. 214:161-85.
4. Yadi H, Burke S, Madeja Z, Hemberger M, Moffett A,
Colucci F. (2008). Unique Receptor Repertoire in Mouse Uterine NK cells. J
Immunol. 181:6140-7.
5. Sharkey AM, Gardner L, Hiby S, Farrell L, Apps R, Masters
L, Goodridge J, Lathbury L, Stewart CA, Verma S, Moffett A (2008). Killer
Ig-like receptor expression in uterine NK cells is biased toward recognition of
HLA-C and alters with gestational age. J Immunol. 181:39-46.
6. Hiby SE, Walker JJ, O'Shaughnessy KM, Redman CWG,
Carrington M, Trowsdale J and Moffett A (2004). Combinations of maternal and
paternal KIR and HLA-C genes influence the risk of pre-eclampsia. Journal of
Experimental Medicine 200, 957-965.
7. Parham P (2004). NK cells and trophoblasts: partners in
pregnancy. J ExpMed. 200:951-5.
Group websites:
www.obgyn.cam.ac.uk/francesco.html
www.trophoblast.cam.ac.uk
www.immunology.cam.ac.uk
