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.2005 Jan;6(1):17-21.
doi: 10.1038/ni1153.

Innate and adaptive immunity: specificities and signaling hierarchies revisited

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Innate and adaptive immunity: specificities and signaling hierarchies revisited

Eric Vivier et al. Nat Immunol.2005 Jan.

Erratum in

  • Nat Immunol. 2005 Feb;6(2):219

Abstract

The conventional classification of known immune responses by specificity may need re-evaluation. The immune system can be classified into two subsystems: the innate and adaptive immune systems. In general, innate immunity is considered a nonspecific response, whereas the adaptive immune system is thought of as being very specific. In addition, the antigen receptors of the adaptive immune response are commonly viewed as 'master sensors' whose engagement dictates lymphocyte function. Here we propose that these ideas do not genuinely reflect the organization of immune responses and that they bias our view of immunity as well as our teaching of immunology. Indeed, the level of specificity and mode of signaling integration used by the main cellular participants in the adaptive and innate immune systems are more similar than previously appreciated.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Strategies of immune recognition.
In addition to the classical 'altered self' recognition of pMHC complexes used by T cells through their TCR, several strategies of immune recognition coexist, sometimes on the same cells. Cells of the innate immune system (as well as some B and T cell subsets) express germline-encoded receptors such as TLR or Nod molecules that can sense infectious non-self molecules,. In addition, NK cells express the cell surface Ly49H molecule that is an activating innate receptor specific for a virus product (m157 encoded by the mouse cytomegalovirus). Immune effectors can also sense cells in distress without direct recognition of the stress inducer. NKG2D is an example of such a receptor for stress-inducible molecules, such as MICA/B and ULBP (also known as RAET) molecules in humans, as well as H60, MULT1 and Rae1 molecules in the mouse. The function of immune effectors (such as NK cell and T cell subsets) is also negatively regulated by recognition of self through engagement of inhibitory receptors. Examples of inhibitory receptors for self include KIR (in humans) and Ly49 (in the mouse), which recognize classical MHC class Ia molecules; CD94-NKG2A, which recognizes nonclassical MHC class Ib molecules (HLA-E in humans and Qa-1 in the mouse); as well as NKRP1 molecules, which interact with members of the Clr family,.
Figure 2
Figure 2. Degeneracy of the TCR antigen-binding site.
The structure of the BM3.3 TCR in complex with two distinct peptides, pBM1 (a) and VSV8 (b), bound to the H-2Kb MHC class I demonstrates some general features of TCR antigen-binding sites,. Amino acid residues are indicated with single-letter code. α, TCRα; β, TCRβ; p, peptide. When the BM3.3 TCR is in complex with both pBM1–H-2Kb and VSV8–H-2Kb ligands, it centers on the peptide residue found at position 6, the only one that is homologous between pBM1 and VSV8. In contrast to the pBM1 peptide, for the VSV8 peptide all the other TCR contact positions found are subject to nonconservative replacements. Replacement at position 7 affects TCR binding in a negative way, whereas the replacement at position 4 was beneficial because of the flexibility of complementarity-determining region 3 (CDR3α). Although CDR3 conformational changes help to explain BM 3.3 TCR binding degeneracy, the BM3.3 TCR can also show exquisite specificity, in that it fails to recognize most analogs of the pBM1 or VSV8 peptides differing at position 6. The MHC class I α1 helix is the green cylinder in the background. BM3.3 CDR3α and CDR3β are thin bars and the interactions they form with the pBM1 and VSV8 peptides are red and blue dotted lines (hydrogen bonds) and gray dotted lines (van der Waals contacts). Reprinted from ref. .
Figure 3
Figure 3. Is a 'two-signal' model of T cell activation still tenable? Signals emanating from the TCR (or the BCR) and the optional signals originating from a vast array of cell surface context detectors converge on intracytoplasmic coincident detectors.
Among the surface context detectors, much attention has focused on the CD28 costimulator. However, signals originating from the antigen receptor core can also be 'tuned' by many costimulators (such as CD5, CD19, NKG2D or integrins) and coinhibitors (such CD5, CD22, FcγRIIb or KIRs). The CD8-CD4 coreceptors constitute intrinsic components of the TCR sensor. It remains a daunting task to understand how the antigen-receptor signaling pathways are regulated through the summation of this multitude of positive and negative inputs.
Figure 4
Figure 4. Cross-talk between ITAM- and TLR-dependent pathways.
Neutrophils and macrophages coexpress TLRs and TREMs (triggering receptors expressed by myeloid cells). TREMs are coupled to the ITAM-bearing polypeptide KARAP (DAP12),. TREMs and TLRs act in synergy for cytokine and chemokine production by monocytes and neutrophils. Moreover, blocking the TREM1 pathwayin vivo stops the development of sepsis. Finally, KARAP (DAP12) and TREM expression is upregulated after TLR4 triggering. Thus, cross-talk exists between TLRs and TREMs, exemplifying the complex integrative network of receptor-dependent pathways that determine cellular specificity.
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