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Mechanisms of Lymphocyte Activation and Immune Regulation X pp 29–39Cite as

Genetic Analysis of Innate Immunity: Identification and Function of the TIR Adapter Proteins

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 560))

Summary

The innate immune system senses pathogens largely through signals initiated by a collection of phylogenetically related proteins known as “Toll-like receptors” (TLRs), of which ten representatives are encoded in the human genome. The sensing role of the TLRs first came to light when one member of this family, TLR4, was shown to serve the detection of endotoxin (lipopolysaccharide; LPS) in mice. This discovery was based upon positional cloning of a spontaneous mutation affecting a locus known as Lps. The recognition specificities of other TLRs have since been established by reverse genetic methods. The understanding of the biochemical circuitry that maintains the innate capacity for immune recognition and response has loomed as the next hurdle in the field. A total of five adapter proteins with cytoplasmic domain homology to the TLRs are known to exist in mammals. These proteins are not entirely promiscuous in their interaction with TLRs, but rather, show preferential association with individual family members, giving a particular character to the signals that distinct micro-organisms initiate. The adaptive immune response is dependent upon upregulation of costimulatory molecules (UCM) such as CD80 and CD86. Very recently, it has been shown that this upregulation is dependent upon an adapter encoded by a locus known as Lps2, known as Trif or Ticam-1, and upon type I interferon receptor signaling. LPS and dsRNA both signal via Trif, but dsRNA has an accessory pathway for UCM, that is independent of both Trif/Ticam-1 and the known dsRNA receptor, TLR3. Other key innate immunity genes have also been disclosed by germline mutagenesis, and are discussed in the present review.

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Authors and Affiliations

  1. Department of Immunology, Scripps Research Institute, IMM-31, 10550 N. Torrey Pines Road, La Jolla, California, 92037

    Bruce Beutler, Kasper Hoebe, Philippe Georgel, Koichi Tabeta & Xin Du

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  1. Bruce Beutler
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  2. Kasper Hoebe
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  3. Philippe Georgel
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Editors and Affiliations

  1. University of California Irvine, Irvine, California

    Sudhir Gupta

  2. NIAID, NIH, Bethesda, Maryland

    William E. Paul

  3. Rockefeller University, New York, New York

    Ralph Steinman

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Beutler, B., Hoebe, K., Georgel, P., Tabeta, K., Du, X. (2005). Genetic Analysis of Innate Immunity: Identification and Function of the TIR Adapter Proteins. In: Gupta, S., Paul, W.E., Steinman, R. (eds) Mechanisms of Lymphocyte Activation and Immune Regulation X. Advances in Experimental Medicine and Biology, vol 560. Springer, Boston, MA. https://doi.org/10.1007/0-387-24180-9_4

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