Target Discovery and Validation Reviews and Protocols

Overview of Immune System 297
the cell by endocytosis (Fig. 9). Thus, proteins released from tumor cells by
secretion, shedding, or tumor lysis are captured by APCs. These antigens are
processed, and peptides are presented to CD4+ cells by MHC class II. Notably,
the majority of class II molecules acquire peptides in a specialized compartment,
the so-called CPL. The synthesized class II molecules reach this compartment
through the early endosomes. A special protein called invariant chain is responsible
for the proper intracellular trafficking of class II molecules and peptides
present in ER (40). Defects in either class I, II, or both types of antigen processing
is one of the mechanisms by which bacteria, viruses, and tumor cells escape the
immune system.
7. T-Cell Activation Requires at Least Two Signals
T-cell activation and differentiation require not only TCR recognition of
the antigen–MHC complex but also co-stimulation through the interaction of
accessory molecules on APCs and their corresponding receptors on
T-lymphocytes (41). Therefore, class I and II presentation of peptide antigens
to T-cells (signal 1) is not enough to induce their activation; coreceptor stimulation
also is required (signal 2), which is delivered by the same APCs (Fig. 10A).
In the absence of signal 2, T-cells are inactivated via energy (Fig. 10B). The
outcome of T-cell responses after of recognition of specific antigens is modulated
by costimulatory signals, which are required for both lymphocyte activation and
development of adaptive immunity. The engagement of the CD28 molecule
expressed on resting T-cells with the shared ligands B7.1 (CD80) and B7.2 (CD86)
on activated APCs enhances the T-cell response. Other costimulatory molecules
include lymphocyte function antigen-1 and -2 (42).
Sustained T-cell activation is expected to cause damage to the organism;
thus, once T-cells are activated, they express additional molecules to modulate
the immune response. Among the best studied of these counterregulatory
pathways is the one initiated by engagement of the cytotoxic T-lymphocyteassociated
antigen (CTLA) 4, which is a homolog to the CD28 and binds to
B7.1 and B7.2 molecules with much higher affinity than CD28 (Fig. 10C).
CTLA4 is induced after T-cell activation and delivers inhibitory signals to T-cells
that oppose the co-stimulatory signals delivered by CD28, leading to attenuation
of T-cell activation late in the immune response (43). Inducible costimulatory
(ICOS) is another member of the CD28 family, and it is not expressed by naive
CD4+ cells, but it is induced after T-cell activation. Programmed death (PD)
receptor ligand (PD-L) 1 (also called B7-H1) is a recently described B7 family
member that binds to PD-1 expressed by T-cells (43). This signaling pathway
has been reported to decrease TCR-induced proliferation and cytokine
production.