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Assumption 3:
Cellular Conflict
Ligands and receptors in different cells of the immune system lead to conflicting
interactions (for instance, while one cell promotes interaction with one other cell, this
other cell may promote interactions with another different cell, provided it is given
the opportunity).
A fourth assumption will also be required in order to render cellular frustration a
functionally powerful mechanism that establishes both tolerance and selective
reactivity against non-self.
Assumption 4:
An effector response takes place only after two cells have been
interacting for a characteristic amount of time.
3 Evidence for Cellular Frustration?
Although no experimental proof of the cellular frustration concept exists, here we
argue that important experimental results are at least consistent with the possibility.
Readers not initially concerned with experimental details may skip this section
without any loss in understanding the model proposed.
Assumption 1: Cellular crossreactivity.
There is extensive experimental evidence
that immune cells display a huge variety in their capacity to interact with other cells.
Dendritic cells (DC), for example, can interact with CD4+ or CD8+ T cells,
regulatory T cells [17], B cells [18], other DC [19], granulocytes [20], Natural Killer
cells [21], or with non-hematopoietic cells, such as splenic stroma cells [22].
There is also wide variety in T cell interactions. CD4
+
T (helper) cells can be
activated by cells that present antigen in the context of class II Major
Histocompatibility Complex (MHC), such as DC, macrophages and B cells. In
addition, T cell function can be stimulated by NK cells [23] and mast cells [24]. T
cells can also contact many different types of target cells in the effector phase.
Cytotoxic T cells for example monitor all the cells of the body. Interestingly, even
neuronal cells have been described to influence T cell function [25].
Interactions among T cells themselves play an important role in regulatory
activities of the immune system. Regulatory T cells can either target effector T cells
directly [26] or modulate the T cell activating capacity of APC [17, 27]. Anergic T
cells in their turn can pass on immune responsiveness by down regulation of other T
cell responses [28, 29]. Moreover, pMHCs from APC can be acquired by T cells and
internalized in such a way that T cells became sensitive to peptide-specific lysis by
neighboring T cells [30]. Hence, immune cells are capable of interacting with a wide
variety of other cells.
Assumption 2: Immune system cells are selective.
During the induction phase of an
immune response it is likely that immune cells encounter a variety of stimulatory
cells. An important question is whether cells in this case select for interaction with
cells that offer the highest stimulus. Regarding the T cell-APC interactions, T cells
were observed to have short interactions with different APC, before engaging in a
long-term interaction with a particular APC [31, 32]. The sequential encounters of T
cells could indicate selection of the APC that offers the strongest stimulus. In favor of
