Ruslan Medzhitov

Toll-like receptors have a crucial role in the detection of microbial infection in mammals and
insects. In mammals, these receptors have evolved to recognize conserved products unique
to microbial metabolism. This specificity allows the Toll proteins to detect the presence of
infection and to induce activation of inflammatory and antimicrobial innate immune responses.

Recognition of microbial products by Toll-like receptors expressed on dendritic cells triggers functional maturation of dendritic cells and leads to initiation of antigen-specific adaptive immune responses.

One of the most fascinating problems in immunology
is understanding how the host organism detects the
presence of infectious agents and disposes of the invader
without destroying self tissues. This problem is not
trivial given the enormous molecular diversity of
pathogens and their high replication and mutation
rates. In response to this challenge,multicellular organisms have evolved several distinct immune-recognition systems. In vertebrate animals, these systems can be broadly categorized as ‘innate’ and ‘adaptive’.
Adaptive immune recognition relies on the generation
of a random and highly diverse repertoire of antigen
receptors — the T- and B-cell receptors (TCR and BCR)
— followed by clonal selection and expansion of receptors
with relevant specificities. This mechanism accounts
for the generation of immunological memory,which
provides a significant adaptive fitness to vertebrate animals.

However, the adaptive immune response has two
main limitations. First, randomly generated antigen
receptors are unable to determine the source and the
biological context of the antigen for which they are specific.
Second, a clonal distribution of antigen receptors
requires that specific clones expand and differentiate into
effector cells before they can contribute to host defence.
As a result, primary adaptive immune responses are
delayed, typically for 4–7 days,which is too much of a
delay to combat quickly replicating microbial invaders.
However, the adaptive immune system does not function
independently. Indeed, almost every aspect of the adaptive
immune response is controlled by a combination of
permissive and instructive signals, which are provided by
the evolutionarily ancient and more universal innate
immune system.As will be discussed, the innate immune
system detects the presence and the nature of infection,
provides the first line of host defence, and controls the
initiation and determination of the effector class of
the adaptive immune response.

Although the innate immune system was first
described by Elie Metchnikoff over a century ago,
progress in its analysis has been largely overshadowed
by the fascinating intricacies of adaptive immunity.
Nevertheless, the discoveries of antimicrobial peptides,
complement and dendritic cells (DCs), as well as studies
in plant and invertebrate immunity, have all greatly contributed to our current understanding of the innate
immune system.The recent discovery and characterization
of the Toll-like receptor (TLR) family have incited
new interest in the field of innate immunity. It is already
clear that these receptors have a vital role in microbial
recognition, induction of antimicrobial genes and the
control of adaptive immune responses. Indeed, recent
studies have shown that TLRs have a crucial role in the
recognition of ‘molecular signatures’ of microbial
infection, in engaging differential signalling pathways,
and in controling DC maturation and differentiation of
T helper (TH) cells.

Innate immune recognition