Immune cells fight infection and cancer. Surprisingly, maternal immune cells in the womb help fetuses to grow. The environment in the womb marks the progeny for life, programming their health and predisposition to disease. Babies born too small, for example, may develop cardiovascular disease later in life.
Elie Metchinikoff’s visionary theory suggested in the 19th century that cells regulating growth and nutrition also defend us from within. Modern immunology seeks to understand how tissue-resident immune cells work and how they intersects with metabolism, microbes, and homeostasis. Our research has two main streams.
1. NATURAL KILLER CELLS AND OTHER INNATE LYMPHOID CELLS
NK cells are part of the most abundant group (known as Group 1) of innate lymphoid cells (ILC) in the uterus. We, and others have found also ILC2 and ILC3 in human and mouse uterus. The lining of uterus is rebuilt hundreds of times during a woman’s lifetime, let alone the dramatic changes occurring during pregnancy and ILCs may regulate uterine tissue homeostasis. Uterine group 1 ILCs contribute to fetal growth through vascular changes in the decidua and the development of the placenta. We focus on understanding how specific sub-populations of uterine ILCs in humans and mice deliver these functions, including how the process known as NK-cell education may impact on fetal growth. We have also discovered that the IL-33-ILC2s axis is key to maintain immune homeostasis in the uterus, thus promoting fetal growth and protecting the fetus from endotoxin-induced abortion.
In parallel, we seek to understand how subpopulation of tissue NK cells and ILCs may function in ovarian cancer.
Variable immune system genes (KIR and HLA) interacting through contacts between maternal NK cells and fetal placental cell may keep the birth weight between the extremes that cause maternal and neonatal disease. Indeed, certain combinations of KIR and HLA genes associate with pregnancy complications, which are more frequent in Sub-Saharan Africa. Pathogens, for example the agent that causes Malaria, may have selected variants that predispose to pregnancy complications. Our lab is testing these hypotheses using data from a large prospective study (POPs) and a large African case-control study. We seek to understand the mechanisms of how the signals triggered by interactions between variants of KIR and HLA-C influence the biology of uNK cells and placental cells. The big challenge is to understand how complex and diverse combinations of genetic variants control phenotypes of heterogeneous tissue NK cells in the context of disease association.
To study our research questions, we use samples from healthy donors and patients with pregnancy complications and ovarian cancer, transgenic mouse models, infection models, Flow and Mass Cytometry, RNA-sequencing, high-resolution genotyping, 3D-micro-CT imaging and more conventional approaches.
For a comprehensive list of publications, visit Dr Colucci’s Google Scholar profile
Filipovic I, Chiossone L, Vacca P, Hamilton R, Ingegnere T, Doisne JM, Hawkes DA, Mingari MC, Sharkey A, Moretta L, Colucci F. Molecular definition of group 1 innate lymphoid cells in the mouse uterus. Nat Comm. 2018. doi.org/10.1101/330068
Woods L, Perez-Garcia V, Kieckbusch J, Wang X, DeMayo F, Colucci F, Hemberger M. Decidualisation and placentation defects are a major cause of age-related reproductive decline. Nature communications. 2017 Sep 5;8(1):352.
Colucci F, Traherne J. Killer-cell immunoglobulin-like receptors on the cusp of modern immunogenetics. Immunology. 2017 Dec;152(4):556-561. doi: 10.1111/imm.12802. Epub 2017 Sep 12. Review.
Colucci F. The role of KIR and HLA interactions in pregnancy complications. Immunogenetics. 2017 Aug;69(8-9):557-565. doi: 10.1007/s00251-017-1003-9. Epub 2017 Jul 10. Review
Moffett A, Chazara O, Colucci F. Maternal allo-recognition of the fetus. Fertil Steril. 2017 Jun;107(6):1269-1272. doi: 10.1016/j.fertnstert.2017.05.001. Review
Gaynor LM, Colucci F. Uterine Natural Killer Cells: Functional Distinctions and Influence on Pregnancy in Humans and Mice. Front Immunol. 2017 Apr 24;8:467. doi: 10.3389/fimmu.2017.00467. eCollection 2017. Review
Kieckbusch J, Gaynor LM, Moffett A, Colucci F. Corrigendum: MHC-dependent inhibition of uterine NK cells impedes fetal growth and decidual vascular remodeling. Nat Commun. 2017 Apr 20;8:15444. doi: 10.1038/ncomms15444.
Tallerico R, Cristiani CM, Staaf E, Garofalo C, Sottile R, Capone M, Pico de Coaña Y, Madonna G, Palella E, Wolodarski M, Carannante V, Mallardo D, Simeone E, Grimaldi AM, Johansson S, Frumento P, Gulletta E, Anichini A, Colucci F, Ciliberto G, Kiessling R, Kärre K, Ascierto PA, Carbone E. IL-15, TIM-3 and NK cells subsets predict responsiveness to anti-CTLA-4 treatment in melanoma patients. Oncoimmunology. 2016 Dec 7;6(2):e1261242. doi: 10.1080/2162402X.2016.1261242. eCollection 2017.
Kennedy PR, Chazara O, Gardner L, Ivarsson MA, Farrell LE, Xiong S, Hiby SE, Colucci F, Sharkey AM, Moffett A. Activating KIR2DS4 Is Expressed by Uterine NK Cells and Contributes to Successful Pregnancy. J Immunol. 2016 Dec 1;197(11):4292-4300. Epub 2016 Nov 4.
Moffett A, Chazara O, Colucci F, Johnson MH. Variation of maternal KIR and fetal HLA-C genes in reproductive failure: too early for clinical intervention. Reprod Biomed Online. 2016 Dec;33(6):763-769. doi: 10.1016/j.rbmo.2016.08.019. Epub 2016 Sep 5.
Colucci F. Imagine a world without borders: an immunologist’s thoughts on Brexit. EMBO Rep. 2016 Sep;17(9):1241. doi: 10.15252/embr.201643019. Epub 2016 Aug 5.
Boulenouar S, Doisne JM, Sferruzzi-Perri A, Gaynor LM, Kieckbusch J, Balmas E, Yung HW, Javadzadeh S, Volmer L, Hawkes DA, Phillips K, Brady HJ, Fowden AL, Burton GJ, Moffett A, Colucci F. The Residual Innate Lymphoid Cells in NFIL3-Deficient Mice Support Suboptimal Maternal Adaptations to Pregnancy. Front Immunol. 2016 Feb 19;7:43. doi: 10.3389/fimmu.2016.00043. eCollection 2016.
Kieckbusch J, Balmas E, Hawkes DA, Colucci F. Disrupted PI3K p110δ Signaling Dysregulates Maternal Immune Cells and Increases Fetal Mortality In Mice. Cell Rep. 2015 Dec 29;13(12):2817-28. doi: 10.1016/j.celrep.2015.11.050. Epub 2015 Dec 17.
Kieckbusch J, Gaynor LM, Colucci F. Assessment of Maternal Vascular Remodeling During Pregnancy in the Mouse Uterus. J Vis Exp. 2015 Dec 5;(106):e53534. doi: 10.3791/53534.
Sottile R, Pangigadde PN, Tan T, Anichini A, Sabbatino F, Trecroci F, Favoino E, Orgiano L, Roberts J, Ferrone S, Kärre K, Colucci F, Carbone E. HLA class I downregulation is associated with enhanced NK-cell killing of melanoma cells with acquired drug resistance to BRAF inhibitors. Eur J Immunol. 2016 Feb;46(2):409-19. doi: 10.1002/eji.201445289. Epub 2015 Dec 20.
Ali TH, Pisanti S, Ciaglia E, Mortarini R, Anichini A, Garofalo C, Tallerico R, Santinami M, Gulletta E, letto C, Galgani M, Matarese G, Bifulco M, Ferrone S, Colucci F, Moretta A, Kärre K, and Carbone E (2014). Enrichment of CD56(dim)KIR+CD57+ highly cytotoxic NK cells in tumour-infiltrated lymph nodes of melanoma patients. Nat. Comms. 5: 5639 DOI 10.1038/ncomms6639
Kieckbusch J, Gaynor LM, Moffett A & Colucci F (2014). MHC-dependent inhibition of uterine NK cells impedes fetal growth and decidual vascular remodelling. Nat Comm 5:3359
Moffett A & Colucci F (2014). Uterine Natural Killer cells: Active regulators at the maternal-fetal interface. J Clin Invest 124(5):1872-1879
Colucci F, Boulenouar S, Kieckbusch J & Moffett A (2011). How does variability of immune system genes affect placentation? Placenta 32(8):539-545
Doisne JM, Tan TC and Colucci F (2011). Guardian of the genome turns on genes that alert natural killer cells. Cell Cycle 10(22):3822-3823
Madeja M, Yadi H, Richard Apps R, Boulenouar S, Roper S, Gardner L, Moffett A, Colucci F & Hemberger M (2011). Paternal MHC expression on mouse trophoblast affects uterine vascularization and fetal growth. PNAS 108(10):4012-4017
Li P, Burke S, Wang J, Chen X, Ortiz M, Lee S, Lu D, Campos L, Goulding D, Ling Ng B, Dougan G, Huntly B, Gottgens B, Jenkins NA, Copeland NG, Colucci F & Liu P (2010). Reprogramming of T Cells to Natural Killer-like cells upon Bcl11b deletion. Science 1126:1188063
Colucci F & Cilio CM (2010). Taming killer cells may halt diabetes progression. Nat Immunol 11:111-112
Lakshmikanth T, Burke S, Ali TH, Kimpfler S, Ursini F, Ruggeri L, Capanni M, Umansky V, Paschen A, Sucker A, Pende D, Groh V, Biassoni R, Hoglund P, Kato M, Shibuya K, Schadenorf D, Anichini A, Ferrone S, Velardi A, Karre K, Shibuya A, Carbone E & Colucci F (2009). NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo. J Clin Invest 119:1251-1263
Saudemont A, Garcon F, Yadi H, Roche-Molina M, Segonds-Pichon A, Martin-Fontecha A, Okkenhaug K & Colucci F (2009). The p110gamma and p110delta isoforms of phosphoinositide 3-kinase differentially regulate natural killer cell migration in health and disease. PNAS 106:5795-5800
Yadi H, Burke S, Madeja Z, Moffett A & Colucci F (2008). Unique receptor repertoire in mouse uterine NK cells. J Immunol 181:6140-6147
Kim N, Saudemont A, Webb, L, Camps M, Ruckle T, Hirsch E, Turner M & Colucci F (2007). The p110delta catalytic isoform of PI3K is a key player in NK-cell development and cytokine secretion. Blood 110:3202-3208
Colucci F (2007). Unexpected partnership between IL-5 and Dap-10. Nat Immunol 8:1289-1291
Caraux A, Kim N, Bell SE, Zompi S, Ranson T, Lesjean-Pottier S, Garcia-Ojeda ME, Turner M & Colucci F (2006). Phoshpolipase C-gamma2 is essential for NK cell cytotoxicity and innate immunity to malignant and virally infected cells. Blood 107:994-1002
Colucci F, Caligiuri MA & Di Santo JP (2003). What does it take to make a natural killer? Nat Rev Immunol 3:413-425
Zompi S, Hamerman JA, Ogasawara K, Schweighoffer E, Tybulewicz VL, Di Santo JP, Lanier LL & Colucci F (2003). NKG2D trigger cytotoxicity in mouse NK cells lacking DAP12 or Syk family kinases. Nat Immunol 4:565-572
Colucci F, Di Santo JP & Leibson PJ (2002). Natural killer cell activation in mice and men: different triggers for similar weapons? Nat Immunol 3:807-813
Colucci F, Schweighoffer E, Tomasello E, Turner M, Ortaldo JR, Vivier E, Tybulewicz VL & Di Santo JP (2002). Natural cytotoxicity uncoupled from the Syk and ZAP-70 intracellular kinases. Nat Immunol 3:288-294
Colucci F, Bergman ML, Penha-Goncalves C, Cilio CM & Holmberg D (1997). Apoptosis resistance of nonobese diabetic peripheral lymphocytes linked to the Idd5 diabetes susceptibility region. PNAS 94:8670-8674