Innate Immunity
The innate immune response is the first line of defense against microbial pathogens. Receptors of the innate immune system recognize specific molecular patterns that are conserved in viral or bacterial pathogens but absent in the host. This recognition event results in the secretion of cytokines, which are required, along with T cell receptor/peptide/MHC complexes, to activate the adaptive immune system. By binding microbial molecular patterns, receptors of the innate immune system therefore couple recognition of infection with the induction of pathogen-specific adaptive immune responses, including B-cell activation (and antibody production), cytotoxic T-cell activation (and lysis of infected cells), and helper T-cell proliferation (and inflammation).

Toll-like receptors
The most important family of receptors involved in molecular pathogen recognition by the innate immune system identified so far is the toll-like receptor (TLR) family. About a dozen TLRs have been found so far in humans. Each TLR appears to bind a specific microbial product, which induces an appropriate response from the adaptive immune system. The ligands for most TLRs have been identified, and span a wide variety of structural motifs, such as lipopolysaccharide (LPS), lipopeptides, bacterial flagellin, CpG DNA, single-stranded RNA, double-stranded RNA and several viral envelope glycoproteins. Remarkably, each TLR recognizes its respective ligand with an extracellular domain that contains 19-25 leucine-rich repeats capped on either end by small N- and C-terminal domains.

NODs and VLRs
Microbial molecular pattern recognition by leucine-rich repeats is not limited to TLRs. The NOD proteins use a leucine-rich repeat domain to recognize bacterial components in the cytoplasm. A similar set of signals is generated when NODs bind ligand as when TLRs bind ligand, so that NODs can be viewed as an intracellular branch of the innate immune system. The variable lymphocyte receptors (VLRs) of the adaptive immune system of the sea lamprey also recognize antigens with leucine-rich repeat domains capped by N- and C-terminal repeats. Insertion of diverse LRR cassettes from a large bank in the lamprey genome into an incomplete germline VLR gene allows individual lymphocytes to express a uniquely rearranged VLR gene that recognizes a specific antigen in monoallelic fashion. How the leucine-rich repeat fold is able to recognize such a large variety of structural motifs remains to be determined and will be the object of our research. We will also try to understand how ligand binding by receptors of the innate immune system is coupled to the induction of adaptive immune responses and why different microbial molecules elicit different responses. This work will be carried out in collaboration with Prof. Ruslan Medzhitov (Yale School of Medicine).

Further reading
Janeway, C.A., Jr. & Medzhitov, R. (2002). Innate immune recognition. Annu. Rev. Immunol. 20, 197-216.

Akira, S., Takeda, K. & Kaisho, T. (2001). Toll-like receptors: critical proteins linking innate and acquired immunity. Nature Immunol. 2, 675-80.

Pancer, Z., Amemiya, C.T., Ehrhardt, G.R.A., Ceitlin, J., Gartland, G.L. & Cooper, M.D. (2004). Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey. Nature 430, 174-80.

Bell, J.K., Mullen, G.E.D., Leifer, C.A., Mazzoni, A., Davies, D.R. & Segal, D.M. (2003). Leucine-rich repeats and pathogen recognition in Toll-like receptors. Trends immunol. 24, 528-33.