Cellular Frustration: A New Conceptual Framework for Understanding Cell-Mediated Immune Responses - Artificial Immune Systems - page 37

Cellular Frustration: A New Conceptual Framework for
Understanding Cell-Mediated Immune Responses
F. Vistulo de Abreu 1,2 , E.N.M. Nolte-'Hoen 2,3 , C.R. Almeida 2 , and D.M. Davis 2
1 Depto. Física, Universidade de Aveiro, 3810 Aveiro, Portugal
[e-mail]
2 Division of Cell and Molecular Biology, Imperial College, London, UK
{d.davis, crda}@imperial.ac.uk
3 Department of Biochemistry and Cell Biology, Utrecht University, The Netherlands
[e-mail]
Abstract. Here we propose that frustration within dynamic interactions
between cells can provide the basis for a functional immune system. Cellular
frustration arises when cells in the immune system interact through exchanges
of potentially conflicting and diverse signals. This results in dynamic changes
in the configuration of cells that interact. If a response such as cellular
activation, apoptosis or proliferation only takes place when two cells interact
for a sufficiently long and characteristic time, then tolerance can be understood
as the state in which no cells reach this stage and an immune response can
result from a disruption of the frustrated state. Within this framework, high
specificity in immune reactions is a result of a generalized kinetic proofreading
mechanism that takes place at the intercellular level. An immune reaction could
be directed against any cell, but this is still compatible with maintaining perfect
specific tolerance against self.
Keywords: self-nonself discrimination, tolerance, homeostasis, cellular
frustration, generalized kinetic proofreading.
1 Introduction
Distinguishing self from non-self is understood in many systems at the level of
specific molecular processes between individual cells. In contrast, relatively little
progress has been made in understanding how the complexity of interactions between
populations of many different cells contribute to the functional discrimination
between self and non-self. Some theoretical models have attempted to study such
complicated interactions at the population level [1-5]. Broadly, present theoretical
models of both innate and adaptive immunity assume that effector functions are
triggered when a non-self pattern is recognized. In all these models, recognition is not
the outcome of an optimization process; rather it is a non-linear (often binary)
response to a pattern. This happens when an antibody binds to an antigen (as modeled
by affinity shape space models [6,7]), or when a T cell detects agonist peptide-MHC
complexes (pMHC) [2,8,9]. High specificity in the recognition process is helped by