Target Discovery and Validation Reviews and Protocols

Overview of Immune System 279
difference in antigen recognition, both B- and T-cell receptors have selected
peptides as their major recognition targets. Cells of innate immunity, such as
macrophages and DCs, produce considerable amounts of cytokines, which play
an essential role in influencing the nature of the adaptive immune responses.
To explain immune tolerance, Polly Matzinger (9) presented the danger
model, which suggests that a specific immune response develops as a result of
danger detection rather than by discrimination between self- and nonself antigens.
This model assumes that what really matters is whether the “antigen”
causes damage. It does not matter if the damage is done by a pathogen or by
self-proteins. Although this model refers mainly to immune tolerance, its
assumptions are valid for tumors. Recently, Charlie Janeway (10) has suggested
that antigen-presenting cells (APCs) and other cells of the innate immune
system express a series of pattern recognition receptors (PRRs) specific for
common motifs expressed by several pathogens. These motifs have been
termed pathogen-associated molecular pattern (PAMP). PAMP recognition by
PRRs, in particular TLRs, enables the innate immune system to distinguish self
from nonself and is important not only for triggering innate immunity against
microbial infection but also for priming the adaptive immune response.
Triggering of PRRs activates the APCs and without this activation, no immune
responses occur. This expanded SNS model assumes that the primary role of
the immune system is to distinguish self-tissues from infectious nonself
tissues, and this ability is necessary even for relatively lower organisms that
have innate immune systems, but not adaptive systems capable of generating
antigen-specific T- and B-lymphocytes. However, this model is not complete in
that it does not account for responses against transplants or tumors. Because
immune tolerance plays a crucial role in tumor immunology, this chapter
describes how tolerant T- and B-cells to self-antigens are generated and activated
in the periphery, and it outlines the technical advances in tumor antigen discovery
and validation.
2. T-Cell Development and Maturation
The main goal of lymphocyte development is to generate a large repertoire
of cells expressing diverse receptors that enable them to recognize and react to
millions of foreign antigens (8). The key challenges of this specific immunity
are to have as broad a repertoire of receptors as possible in the absence of potentially
harmful autoreactive lymphocytes. In most adult vertebrates, the bone
marrow contains hematopoietic stem cells (HSCs) that can differentiate into
progenitors with more restricted lineage and that are capable for generating all
blood cell types via commitment events (Fig. 1).
Despite their different roles in the immune response, T-helper (Th) CD4+
cells and CD8+ cytotoxic T (Tc) cells originate from a common precursor (11).