Target Discovery and Validation Reviews and Protocols

298 Sioud
In contrast to the expression of B7.1 and B7.2, PD-1 ligands are expressed
not only on hematopoietic cells but also in nonlymphoid organs. The expression
of PD-L1 and PD-L2 within nonlymphoid tissues suggests that these PD-1 ligands
may modulate the autoreactivity of T- and B-cells in peripheral tissues.
However, interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T-cells
may induce T-cell tolerance, leading to tumor escape. Together, these observations
underlie the crucial role played by APCs in controlling T-cell activation
and in determining the outcome of the immune responses whether directed
against self or nonself.
8. T- and B-Cell Collaboration
Cross-linking of surface immunoglobulin by exogenous protein antigens
can activate B-cells; however, this activation is not normally sufficient on its
own to activate their proliferation and differentiation into plasma and memory
B-cells. B-cell responses to these antigens are driven by interactions with
a specialized subset of T-cells, namely, the helper T-cells (44). Thus, exogenous
antigen, which is recognized by the surface IgM on the B-cell, is internalized,
processed, and reexpressed on the MHC class II molecule of the
B-cell (Fig. 6). This B-cell can then present the antigen to a primed specific
T-cell. When stimulated, the T-cell expresses CD40 ligand, which binds to
CD40 on the B-cell, and the T-cell produces cytokines, leading to B-cell
division and maturation to antibody-secreting plasma cells (45). T-cell interaction
induces isotype switching from the initial IgM response. As soon as
the isotype switch from IgM to another higher affinity antibody (IgG, IgA,
and IgE) has occurred, some of the activated cells become long-lived memory
cells. Memory is a characteristic hallmark of the adaptive immune
response, thus making the host cells prepared to mount a more powerful
immune response when they encounter the pathogen for the second time.
Cooperation between both arms of the immune system is essential to produce
optimized immune responses capable for eradicating infections. As
mentioned above (see Fig. 6), B-cells also can respond to some antigens in
a T-cell–independent manner by cross-linking of the receptors. However,
these responses are limited to IgM, of poor affinity, and are short lived.
9. Th1 and Th2 Type Responses
Subsequent to T-cell development, two major types of effector T-cells are
generated, Th cells bearing CD4 molecules on their surface and Tc cells bearing
CD8 molecules (Fig. 3). CD4+ T-cells only recognize antigen presented with
MHC class II and CD8+ T-cells with MHC class I. CD4+ Th cells recognize
foreign antigen and activate other parts of the cell-mediated immune response
to eradicate the pathogen. They also play a major part in activation of B-cells