Target Discovery and Validation Reviews and Protocols

278 Sioud
gene products have been described in cancer patients (2,3). Moreover, we and
others have shown that a high number of T-cells are present within tumors and
that these cells are specifically recruited to tumor beds (4,5). In addition, T-cells
reactive with tumor antigens are present in the peripheral blood and lymph
nodes of diverse patients. Collectively, these results indicate that the immune
system can recognize cancer cells. However, despite their potential immunogenicity,
tumor antigens do not induce significant immune responses, which
could destroy malignant cells; therefore, a central question is whether recognition
of tumor antigens by immune cells would mainly lead to tolerance.
The different mechanisms for recognition and elimination of pathogens have
been divided in the immune system into “innate immunity,” which encompasses
the presumably more primitive elements of the system, including macrophages,
natural killer (NK), and antigen-presenting cells, and “adaptive immunity,”
which encompasses T- and B-lymphocytes. The activation of innate immunity is
mainly mediated by the recognition of potential pathogens by Toll-like receptors
(TLRs) that are mainly expressed on immune cells such as macrophages, dendritic
cells (DCs), and monocytes (6,7). These receptors function as sensors of infection
and induce the activation of innate and adaptive immune responses. Upon
recognizing conserved structures, which are referred to as pathogen-associated
molecular patterns (PAMPs), TLRs activate host defense responses through
their intracellular signaling domain, the Toll/interleukin-1 receptor (TIR) domain,
and the downstream adaptor protein MyD88. Although members of the TLRs
all signal through MyD88, the signaling pathways induced by individual receptors
differ (7). So far, 10 TLRs have been described in humans, and ligands have
been defined for nine of these TLRs. TLR1 and -2 are activated by triacylated
lipoproteins, TLR3 by double-stranded viral RNA, TLR4 by lipopolysaccharide
(LPS), TLR5 by bacterial flagellin, TLR2 and -6 by diacylated lipopeptides,
TLR7 and -8 by imidazoquinolines and single-stranded RNA, and TRL9 by
unmethylated bacterial CpG DNA sequences (7). Upon activation, TLRs trigger
the release of cytokines and the induction of co-stimulatory molecules that
can influence the nature of the adaptive T- and or B-cell responses. Activation
of TLRs also induces antimicrobial pathways that kill intracellular organisms
(6–8). Although the innate response is rapid, the response sometimes damages
normal tissues, leading to severe diseases, such a sepsis.
Adaptive immunity is the hallmark of the immune system in higher animals.
It uses antigen-specific receptors expressed on T- and B-cells. The receptors on
B-lymphocytes are Igs, which can be secreted by corresponding plasma cells
after antigenic stimulation. Bound and secreted Igs can bind to a variety of
soluble as well as cell-bound antigens, such as virus proteins. In contrast to
B-cells, T-cells recognize only processed antigens that are presented as peptides
by major histocompatibility complex (MHC) class I or II. Despite this