Antigen families

Pattern recognition receptors (PRRs) are ancestral germline-encoded molecules that enable the organism to detect highly conserved structures of microbes and altered self. Danger signals thus perceived alert both innate and adaptive components of the immune system to mount the most appropriate response.
Major classes of PRRs are the C-type lectin receptors (CLRs), whose key importance in the immune system has recently been recognized (1). Interest in these molecules has particularly been fueled by the discovery that they are broadly represented on DCs, reflecting the positioning of this cell type as sensors at the interface of the immune system and the external environment (2).
CLRs perform a variety of essential functions in DCs.
First, the extracellular portion of CLRs feature one or several carbohydrate-recognition domains (CRDs) which enable binding to sugar moieties present on glycosylated antigens of self-tissue or invading microorganisms. CLRs can bind to monosaccharides as well as complex N- or O-linked glycosylation forms.
By virtue of the particular motifs within their intracytoplasmic tail, most CLRs subsequently internalize bound antigen through receptor-mediated endocytosis.
CLRs with antigen-receptor function in conventional DCs include the macrophage mannose receptor (mAb DENDRITICS), DEC205/CD205 (mAb DENDRITICS), DC-SIGN-like (mAb DENDRITICS), DC-ASGPR (MGL)/CD301 (mAb DENDRITICS: DDX0010, DDX0011) (3), Dectin-1, Langerin/CD207 (4) (mAb DENDRITICS), whereas pDCs utilize the CLR CD303 (mAb DENDRITICS) restricted to this DC subtype (5).
Antigen-capture by CLRs in the absence of a strong DC activation signal can lead to immune tolerance (6), a likely indication of the importance these receptors play to maintain homeostatic control to avoid autoimmunity to damaged self tissue.
A variety of pathogens, including HIV (7, 8) have been reported to bind to CLRs expressed by DCs. However, it is increasingly clear that pathogens have often evolved to subvert the function of host CLRs by inhibition of antigen presentation or modification of T cell responses to evade the immune system (9, 10).
Antigens associated with tumors often display aberrant glycosylation patterns. It has recently been demonstrated that DCs can recognize such modifications through their CLRs (11), opening up new perspectives for cancer immunotherapy. Taken together, it will be of considerable interest to evaluate to which extent CLRs can be manipulated for therapeutic strategies. It is noteworthy that some CLRs, such as DCIR (12) (mAb DENDRITICS) contain a potential immunosuppressive intracytoplasmic ITIM motif, while others (eg Dectin-1) are associated with an immunostimulatory function through the recruitment of ITAM-like motifs.
Finally, it has recently become apparent that the balance between immune silencing and activation is controlled by signaling crosstalk between the CLR and the Toll-like receptor (TLR) (mAb DENDRITICS) pathways (13, 14, 15).
 
References
1. W I. Weis, M E. Taylor, K Drickamer, The C-type lectin superfamily in the immune system, 1998 Immunol Rev 163: 19-34
2. Figdor CG, van Kooyk Y, Adema GJ., C-type lectin receptors on dendritic cells and Langerhans cells, 2002 Nature Rev Immunol 2: 77-84
3. Valladeau J, Duvert-Frances V, Pin JJ, Kleijmeer MJ, Ait-Yahia S, Ravel O, Vincent C, Vega F Jr, Helms A, Gorman D, Zurawski SM, Zurawski G, Ford J, Saeland S.
Immature human dendritic cells express asialoglycoprotein receptor isoforms for efficient receptor-mediated endocytosis., 2001 J Immunol 167: 5767-5774
4. Valladeau J, Duvert-Frances V, Pin JJ, Dezutter-Dambuyant C, Vincent C, Massacrier C, Vincent J, Yoneda K, Banchereau J, Caux C, Davoust J, Saeland S. The monoclonal antibody DCGM4 recognizes Langerin, a protein specific of Langerhans cells, and is rapidly internalized from the cell, 1999 Eur J Immunol 29: 2695-2704
5. Dzionek A, Sohma Y, Nagafune J, Cella M, Colonna M, Facchetti F, Gunther G, Johnston I, Lanzavecchia A, Nagasaka T, Okada T, Vermi W, Winkels G, Yamamoto T, Zysk M, Yamaguchi Y, Schmitz J., BDCA-2, a novel plasmacytoid dendritic cell-specific type II C-type lectin, mediates antigen capture and is a potent inhibitor of interferon alpha/beta induction. 2001 J Exp Med 194: 1823-1834
6. Hawiger D, Inaba K, Dorsett Y, Guo M, Mahnke K, Rivera M, Ravetch JV, Steinman RM, Nussenzweig MC., Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. 2001 J Exp Med 194: 769-779
7. Geijtenbeek TB, Kwon DS, Torensma R, van Vliet SJ, van Duijnhoven GC, Middel J, Cornelissen IL, Nottet HS, KewalRamani VN, Littman DR, Figdor CG, van Kooyk Y., DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells 2000 Cell 100: 587-59
8. Turville SG, Cameron PU, Handley A, Lin G, Pohlmann S, Doms RW, Cunningham AL., Diversity of receptors binding HIV on dendritic cell subsets 2002 Nat Immunol 3: 975-83
9. van Kooyk and Geijtenbeek, DC-SIGN: escape mechanism for pathogens. 2003 Nat Rev Immunol 3: 697-709
10. van Kooyk Y, Engering A, Lekkerkerker AN, Ludwig IS, Geijtenbeek TB., Pathogens use carbohydrates to escape immunity induced by dendritic cells, 2004 Curr Opin Immunol 16: 488-93
 11. van Gisbergen KP, Aarnoudse CA, Meijer GA, Geijtenbeek TB, van Kooyk Y., Dendritic cells recognize tumor-specific glycosylation of carcinoembryonic antigen on colorectal cancer cells through dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin, 2005 Cancer Res 65: 5935-49
12. Bates EE, Fournier N, Garcia E, Valladeau J, Durand I, Pin JJ, Zurawski SM, Patel S, Abrams JS, Lebecque S, Garrone P, Saeland S. APCs express DCIR, a novel C-type lectin surface receptor containing an immunoreceptor tyrosine-based inhibitory motif., 1999, J. Immunol 163: 1973-1983
13. G D. Brown1, J Herre1, D L. Williams2, J A. Willment1, A S. J. Marshall1 and S Gordon1, Dectin-1 mediates the biological effects of beta-glucans». 2003, J Exp Med 197: 1119-1124
14. Gantner BN, Simmons RM, Canavera SJ, Akira S, Underhill DM., 2003 Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor J Exp Med 197: 1107-1117
15. Geijtenbeek TB, Van Vliet SJ, Koppel EA, Sanchez-Hernandez M, Vandenbroucke-Grauls CM, Appelmelk B, Van Kooyk Y., Mycobacteria target DC-SIGN to suppress dendritic cell function. 2003 J Exp Med 197: 7-17