Immune Regulation
Inhibitory receptors in the immune system
@
Linde Meyaard
To prevent auto-immunity and overactivation, the immune system employs several inhibitory mechanisms, among which inhibitory immune receptors. We study the biology and mechanism of inhibitory immune receptors in health and disease, using in vivo and in vitro models, and in collaboration with clinical groups, in patients.
A large part of our published work focuses on LAIR-1. We recently did the important discovery that LAIR is a collagen receptor and that binding of collagens to immune cells can lead to inhibition of cell function. Importantly, we demonstrated that collagens are functional ligands for LAIR-1 and directly inhibit immune cell activation in vitro. We are studying the relevance of this interaction in peripheral tolerance, hematopoiesis and its possible role in tumor immune evasion. Furthermore, in fruitful collaborations with proteins chemists and structural biologists we mapped the LAIR-1-collagen interaction with peptide mapping, crystallography, NMR and mutational analysis. This lead to important basic knowledge which will enable rational design of therapeutics targeting this interaction in future.
The family of inhibitory immune receptors is still expanding. From database homology searches we have identified a novel inhibitory receptor, expressed mainly on phagocytes. We have named this receptor SIRL-1 (Signal Inhibitory Receptor on Leukocytes-1) and are currently characterizing its function and are pursuing the identity of its ligand to understand its biological function.
In addition to the large group of ITIM-bearing receptors, immune cell function can be inhibited by receptors that do not contain these motifs. Examples of non-ITIM bearing inhibitory receptors are CTLA-4 and CD200-receptor (CD200R). CD200R was previously advertised mainly as an inhibitory receptor for myeloid cells. We have found that the receptor can also be expressed on B and T lymphocytes. Our functional studies on this receptor revealed the novel and interesting concept that inhibitory receptors are also needed to control anti-viral immune responses. We have challenged CD200 knock out mice with influenza and observed a striking lethal pathogenesis, different from wild type mice, most likely due to inappropriate immune activation and immunopathology. Interestingly, development of disease was completely prevented by depletion of T cells before infection, despite dramatically increased viral load, indicating that T cells are essential for the development of disease symptoms. Our data show that lack of CD200-CD200R signaling increases immune pathology during influenza infection, which can be reduced by T cell depletion.
Taken together, our studies are aimed to understand the biology and mechanism of inhibitory receptors and might provide an explanation for their differential effects on cell function. This will help understand why so many inhibitory receptors exist and may provide a handle for manipulating the function of specific receptors with therapeutics.
Members- Tomasz Rygiel, Post-Doc
- Guruswamy Karnam, PhD student
- Marloes Olde Nordkamp, PhD student
- Kristof Van Avondt, PhD student
- Margreet Westerlaken, Technician
- Amelia Lacna, Technician
- Arwen Altenburg, Master student
LAIR-1, a novel inhibitory receptor expressed on human mononuclear leukocytes.L. Meyaard, G.J. Adema, C. Chang, E. Woollatt, G.R. Sutherland, L.L. Lanier and J.H. Phillips..
Immunity. 1997, 7:283-290.
Collagens are functional, high affinity ligands for the inhibitory immune receptor LAIR-1 Lebbink RJ, de Ruiter T, Adelmeijer J, Brenkman AB, van Helvoort JM, Koch M, Farndale RW, Lisman T, Sonnenberg A, Lenting PJ, Meyaard L
J Exp Med. 2006 Jun 12;203(6):1419-25. Epub 2006 Jun 5
The inhibitory collagen receptor LAIR-1 (CD305).Meyaard L.
J Leukoc Biol. 2008 Apr;83(4):799-803. Epub 2007 Dec 6. Review.
Lack of CD200 enhances pathological T cell responses during influenza infection.T.P. Rygiel, E.S.K. Rijkers, T. de Ruiter, E.H. Stolte, M. van der Valk, G.F. Rimmelzwaan, L. Boon, A.M. van Loon, F.E. Coenjaerts, R.M. Hoek, K. Tesselaar, and L. Meyaard. 2009.
J. Immunol. 183:1990-1996.
Crystal structure and collagen-binding site of immune inhibitory receptor LAIR-1; unexpected implications for collagen binding by platelet receptor GPVI
T.H.C. Brondijk, T. de Ruiter, J. Ballering, H. Wienk, R.J. Lebbink, H. van Ingen, R. Boelens, R.W. Farndale, L. Meyaard and E.G. Huizinga. Blood 2010. 115:1364-1373.
Signal Inhibitory Receptor on Leukocytes-1 (SIRL-1) is a novel functional inhibitory immune receptor expressed on human phagocytes.T.A.M. Steevels, R.J. Lebbink, G.H.A.Westerlaken, P.J. Coffer and L. Meyaard. 2010.
J. Immunol. 2010 May 1;184(9):4741-8
Co-expression of collagen receptors LAIR-1 and GPVI on a subset of megakaryoblasts.
T.A.M. Steevels, G.H.A. Westerlaken, M.Tijssen, P.J. Coffer, P.J. Lenting, J.W. Akkerman and L. Meyaard. 2010.
Haematologica. 2010 Aug 16.Immune inhibitory receptors: essential regulators of phagocyte function.
T.A.M. Steevels and L. Meyaard. 2011.
Eur J Immunol. 41:575-587.
Enhanced secretion of Leukocyte-Associated Immunoglobulin-like Receptor (LAIR)-2 and soluble LAIR-1 in rheumatoid arthritis: LAIR-2 is a more efficient antagonist of the LAIR-1-collagen inhibitory interaction than soluble LAIR -1.
M.J.M. Olde Nordkamp, J.A.G. van Roon, M. Douwes, T. de Ruiter, R.T. Urbanus and L. Meyaard. 2011.
Arthritis Rheum. Accepted for publication.
2006-2013
Dutch Rheumatoid Arthritis Foundation
2009-2013
NWO-ALW
2010-2011
Infection and Immunity Center Utrecht (IICU) Seeding Grant (with R. de Groot)