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

234 11 Hybrid Cell Vaccination for Cancer Immune Therapy
and 4±1BB [85±88], or they may be activation-induced such as the cytokines IL-2 and
interferon (IFN)-g and their receptors or CD40 and CD40 ligand [75, 89±97]. The expression
of cytokines, IL-2 as growth and differentiation factor for cytotoxic T lymphocytes
(CTLs) provided by the helper T cell [71±73, 75, 76, 90], and IFN-g, a major
differentiation factor of CTLs which can be produced by both T cells types [74, 91,
98, 99], is strictly activation-dependent. Moreover, also the capacity to respond to the
cytokines, i. e. the expression of high-affinity cytokine receptors is induced by the activation
of the T cell via its antigen receptor [89, 90, 100±102]. Recent reports suggest
that additional constitutional or activation-induced factors regulate the interaction of
the APC and the precursor cytotoxic T cell, although their exact molecular nature or
mode of action has not been clarified [103]. It thus appears that the molecular and
cellular mechanisms of the induction and activation of cytotoxic effector T cells have
not yet been completely uncovered. Still, new players are discovered and are added
to the list or are implicated by indirect evidence. The factors so-far identified provide
signals of very different nature acting as co-stimulating factors that affect survival,
growth, differentiation, and mode and extent of the molecular and cellular responses
of the T cells. All these signals are essential for the development of cellular immunity.
The activation of some of these receptors without simultaneous activation of
certain other receptors often results in anergy or activation-induced cell death rather
than activation and maturation [92]. An example of such adverse signaling is the activation
of T cells without involvement of CD28, which among many other effects results
in a block of signaling via the IL-2 receptor. IL-12, on the other hand, is a cytokine
that can block cell death and anergy, and might be critical for sustained expansion
and functional capacity of the activated T cell [25]. It thus appears critical not
only to address the T cell receptors of the interacting T cells, but also to arrange the
cellular and molecular components required for induction of cytotoxic T cells such
that cytotoxic precursor cells and helper T cells are attracted and activated in a coordinated
way involving all the essential co-stimulating factors and receptors [104, 105].
Although several MHC class II-expressing cells can serve as APCs in these three cell
interactions, the DC is clearly the most potent cell for antigen harvesting, processing
and presentation, for organizing the regulatory cell clusters, and for co-stimulation
[97, 106±108]. The cellular interactions involved are dynamic in nature with the cells
responding pair-wise to be modulated and responsive to productive interaction with
the third partner. A recent series of publications have reported that DCs, upon antigen-dependent
interaction with helper T cells, become charged to provide crucial costimulating
signals to the CD8 + T cell [93, 95, 96]. The exact nature of the molecular
factors and interactions that regulate these events still awaits elucidation. In contrast
to the multiple regulatory interactions required for the induction of cytotoxic T cells,
the execution of the effector functions, i.e. the cytolysis of the target cells, is only dependent
on MHC/peptide complexes and cell adhesion. In addition to the requirement
for specific APCs, it seems that the environment where the interacting cells
meet, the lymphoid organs, is also important. The impact of the specific architecture
of the lymphoid organs on the efficiency of the interactions and of the induction of
effector T cell is largely unexplored. However, non-lymphoid tissue appears to be a
far less potent promoter of immune responses [109].