Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

11.2 Immunological Basis of the HCV Approach to Cancer Immune Therapy
mor cells with regard to antigen expression. Differences in the expression of TAAs
have been described for melanoma within single lesions, between different lesions
of the same patient as well as in the same patient at different times in the course of
the disease.
11.2.2
T±T Cell Collaboration in the Induction of Cellular Cytotoxic Immune Responses
The dependence of the induction, activation and expansion of MHC class I-restricted,
CD8 + T cells on T cell help has long been suggested by the crucial role of interleukin
(IL)-2 as growth factor for these cells [36, 71±75] and the finding that activated
MHC class II-restricted CD4 + T cells are the main source for this cytokine [76].
Raulet and Bevan [77], and later Juretic et al. [78] have studied the immunogenetics
of the induction of cytotoxic T cells in further detail, and found that these responses
are MHC class I- as well as MHC class II-restricted, again suggesting a crucial role
of CD4 + T cells in the induction of CD8 + T cell responses. Initially T cell help was
seen as paracrine delivery of IL-2 by the helper T cell to the cytotoxic precursor cell
[75]. It was believed that the efficacy of paracrine IL-2 was dependent on the microenvironment
in which induction of the cytotoxic T cell takes place and a relatively
close proximity of the two cells.
More detailed studies by Mitchison et al. [79, 80] and by our group [81] on the mode
of interaction of helper and cytotoxic precursor T cells have yielded evidence for the
direct involvement of the stimulator or APC in this interaction. Effective interaction
of the two T cell types requires that the APC expresses MHC class I as well as MHC
class II molecules and T cell epitopes for both T cell types [79±83]. Thus, it is the APC
that organizes the interaction of the helper and effector compartment of cellular immunity.
In analogy to the epitope linkage requirement for induction of T cell-dependent
B cells, there is an epitope linkage requirement for the T±T cell collaboration in
the induction of cellular cytolytic T cell responses with the APC linking the two epitopes
[79, 81]. However, a number of studies have shown that the antigens for the
two interacting T cells need not to be related on the molecular level [81, 82]. Thus,
there is a 2-fold MHC restriction and potentially 2-fold antigen specificity that controls
the induction of cytotoxic T cell responses in contrast to T±B cell collaboration
for induction of secondary antibody responses, which is controlled solely by MHC
class II molecules, and where the T and B cell epitopes need to be linked in a single
antigen molecule [84]. This complex mode of antigenic and co-stimulatory control of
the induction of cytolytic effector T cell responses provides additional protection
against potential autoimmune reactions, but also poses restrictions on the induction
of cellular immunity where it is needed, as in the case of cancer or viral infections.
Recognition of cognate peptides together with their specific MHC class I and II molecules
on the surface of the APC by the two T cell types induces a complex array of
molecular interaction between the cells. Both T cells communicate with the APC and
with each other via cell surface molecules and soluble factors. Some of these molecules
are constitutively expressed; others are induced or modulated in their expression.
They may be a result of the maturation of the participating cells as CD28, B7
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