18 Interaction of Pathogens with the Innate and Adaptive Immune System

Dynamics of Listeria infection in normal and SCID mice. In normal mice there is exponential growth and the infection is controlled. The cells involved at different stages are indicated. In SCID mice, the absence of lymphocytes results in persistence of the infection. The early components of the infection involve neutrophils and NK cells, while lymphocytes are essential for clearance of the infection.

General features of a class I MHC molecule. The α1 and α2 domains create the peptide-binding site, which is on top of the molecule. The α3 domain is an Ig-like domain. A small polypeptide, β2-microglobulin, forms part of the complex. (In the class II MHC molecule, the combining site is formed by the two most external domains of the α and β chains, which make up a structure similar to the combining site of class I molecules.)

Structure of a peptide bound to the combining site of a class II MHC molecule. This specific example shows a lysozyme peptide bound to the murine I-Ak molecule. The peptide is stretched out and slightly twisted. The TCR contacts some of the solvent-exposed residues as well as the helices of the α1 (top) and β1 (below) domains. Adapted from D. H. Fremont, D. Monnaie, C. A. Nelson, W. A. Hendrickson, and E. R. Unanue, Immunity 8:305, 1998.

Regulation of CD4 T-cell differentiation. Reprinted from A. O'Garra, Immunity 8:275–283, 1998.

Pathogen-activated innate immune pathways in Drosophila and mammalian cells. In Drosophila (left panel) gram-positive bacteria are recognized by two PRRs, PGRP-SA and GNBP1, which trigger the activation of a proteolytic cascade that activates Spaetzle. A cleaved form of Spaetzle directly activates Toll. The signal is transmitted through a Drosophila homologue of MyD88 (DMyD88) and an IRAK-like protein kinase (Pelle), leading to phosphorylation of the IκB-homologue Cactus, the nuclear translocation of the NF-κB homologues Dif and Dorsal and the activation of Drosophila immune-responsive genes, including antimicrobial peptide genes. In mammals (right panel) PAMPs associated with various extracellular pathogens elicit the activation of TLRs, which can transmit the signal through two TIR containing proteins: MyD88, which activates NF-κB and MAPK pathways leading to up-regulation of several immune responsive genes including proinflammatory cytokines and costimulatory molecules, and TRIF, triggering the IRF-3/interferon β response. Peptidoglycan (PG) associated with intracellular bacteria is recognized by NOD1 and 2, which activate NF-κB pathway through RICK. Abbreviations: PAMPs, pathogen-associated molecular patterns; TLRs, Toll-like receptors; LRR, leucinerich repeat domain; TIR, Toll-IL1 receptor domain; DD, death domain; CARD, caspase activation and recruitment domain; RHD, Rel homology domain; ANK, ankyrin repeats domain; K, kinase domain; IRAK, IL1-receptor-associated kinase; TRAF, TNF-receptor-associated kinase; NF-κB: nuclear factor κB; IκB, inhibitor of κB; IKK: IκB kinase; MAPK, mitogen-activated protein kinase; IFN, interferon; PGRP, peptidoglycan recognition protein; GNBP, gram-negative binding protein.