Andrew McKenzie

Transgenic models of immune and haematopoietic disorders

anm@mrc-lmb.cam.ac.uk

Regulation of the immune system is fundamental to protecting the host from infection whilst constraining autoimmunity, undesirable inflammation and immunopathology. Immune dysregulation can lead to diseases such as asthma and allergy (Figure 1), autoimmunity and leukaemia.

Using techniques including mouse genetics, fluorescence imaging and gene expression analysis we discovered group 2 innate lymphoid cells (ILC2s) as significant new participants in immune regulation through their cytokine secretion (Figure 2). We now know that ILC2s belong to a larger family of ILCs that develop from lymphoid precursors that also give rise to the T and B cell lineages. We aim to identify the transcriptional pathways that regulate this differentiation and gain molecular insight into cell commitment.

ILC2s localise predominantly at mucosal surfaces where they act as critical sentinels for tissue damage and infection, at the interface of innate and adaptive immunity. Our goal is to determine the cellular and molecular pathways that regulate ILCs during homeostasis and disease, and how they might be targeted therapeutically in humans.

Figure 1. Expression of the ILC2-stimulating cytokine interleukin-33 (green) by pneumocytes (red/yellow) in allergen-challenged lung. Cell nuclei are blue.

Figure 2. Influx of T cells (red) and IL-13-producing ILC2s (green), in the lung during an inflammatory response

Selected Papers

Rana B.M.J., Jou E., Barlow J.L., Rodriguez-Rodriguez N., Walker J.A., Knox C., Jolin H.E., Hardman C.S., Sivasubramaniam M., Szeto A., Cohen E.S., Scott I.C., Sleeman M.A., Chidomere C.I., Cruz Migoni S., Caamano J., Jorgensen H.F., Carobbio S., Vidal-Puig A., McKenzie A.N.J. (2019)
A stromal cell niche sustains ILC2-mediated type-2 conditioning in adipose tissue.
J Exp Med. 16(9): 1999-2009.
Walker J.A., Clark P.A., Crisp A., Barlow J.L., Szeto A., Ferreira A.C.F., Rana B.M.J., Jolin H.E., Rodriguez-Rodriguez N., Sivasubramaniam M., Pannell R., Cruickshank J., Daly M., Haim-Vilmovsky L., Teichmann S.A., McKenzie A.N.J. (2019)
Polychromic Reporter Mice Reveal Unappreciated Innate Lymphoid Cell Progenitor Heterogeneity and Elusive ILC3 Progenitors in Bone Marrow.
Immunity. 51(1): 104-118.
Halim T.Y.F., Rana B.M.J., Walker J.A., Kerscher B., Knolle M.D., Jolin H.E., Serrao E.M., Haim-Vilmovsky L., Teichmann S.A., Rodewald H.R., Botto M., Vyse T.J., Fallon P.G., Li Z., Withers D.R., McKenzie A.N.J. (2018)
Tissue-Restricted Adaptive Type 2 Immunity Is Orchestrated by Expression of the Costimulatory Molecule OX40L on Group 2 Innate Lymphoid Cells.
Immunity 48(6): 1195-1207.
Walker J.A., McKenzie A.N.J. (2018)
TH 2 cell development and function.
Nat Rev Immunol. 18(2): 121-133.
Damgaard R.B., Walker J.A., Marco-Casanova P., Morgan N.V., Titheradge H.L., Elliott P.R., McHale D., Maher E.R., McKenzie A.N.J., Komander D. (2016)
The Deubiquitinase OTULIN Is an Essential Negative Regulator of Inflammation and Autoimmunity
Cell 166(5): 1215-1230.
Eberl G., Colonna M., Di Santo J. and McKenzie A.N.J. (2015)
Innate Lymphoid Cells: a new paradigm in immunology.
Science 348(6237): aaa6566.

Group Members

Paula Clark
Ana Carolina Ferreira
Mayuri Gogoi
Morgan Heycock
Helen Jolin
Eric Jou
Sophie Kitching
Martin Knolle
Michelle Ko
Jonathan Mannion
Noe Rodriguez
Aydan Szeto