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.
Preview
Unable to display preview. Download preview PDF.
Similar content being viewed by others
References
Casal, A., Sumen, C., Reddy, T.E., Alber, M.S., Lee, P.P.: Agent-based modeling of the context dependency in T cell recognition. Journal of Theoretical Biology 236(4), 376–391 (2005)
Leon, K., Lage, A., Carneiro, J.: Tolerance and immunity in a mathematical model of T-cell mediated suppression. Journal of Theoretical Biology 225(1), 107–126 (2003)
Chan, C., Stark, J., George, A.J.T.: The impact of multiple T cell-APC encounters and the role of anergy. J. Comp. App. Mathematics 184(1), 101–120 (2005)
Leon, K., Perez, R., Lage, A., Carneiro, J.: Three-cell interactions in T cell-mediated suppression? A mathematical analysis of its quantitative implications. Journal of Immunology 166(9), 5356–5365 (2001)
Leon, K., Perez, R., Lage, A., Carneiro, J.: Modelling T-cell-mediated suppression dependent on interactions in multicellular conjugates. Journal of Theoretical Biology 207(2), 231–254 (2000)
Perelson, A.S., Weisbuch, G.: Immunology for physicists. Reviews of Modern Physics 69(4), 1219–1267 (1997)
Varela, F.J., Coutinho, A.: 2nd Generation Immune Networks. Immunology Today 12(5), 159–166 (1991)
Chao, D.L., Davenport, M.P., Forrest, S., Perelson, A.S.: A stochastic model of cytotoxic T cell responses. Journal of Theoretical Biology 228(2), 227–240 (2004)
Scherer, A., Noest, A., de Boer, R.J.: Activation-threshold tuning in an affinity model for the T-cell repertoire. Proc. Roy. Soc. B 271(1539), 609–616 (2004)
Van Den Berg, H.A., Rand, D.A., Burroughs, N.J.: A reliable and safe T cell repertoire based on low-affinity T cell receptors. Journal of Theoretical Biology 209(4), 465–486 (2001)
McKeithan, T.W.: Kinetic Proofreading in T-Cell Receptor Signal-Transduction. Proceedings of the National Academy of Sciences of the United States of America 92(11), 5042–5046 (1995)
Chan, C., George, A.J.T., Stark, J.: T cell sensitivity and specificity - Kinetic proofreading revisited. Discrete and Continuous Dynamical Systems-Series B 3(3), 343–360 (2003)
Ji, Z., Dasgupta, D.: Real-Valued Negative Selection Algorithm with Variable-Sized Detectors. In: Deb, K., et al. (eds.) GECCO 2004. LNCS, vol. 3102, pp. 287–298. Springer, Heidelberg (2004)
Bersini, H., Calenbuhr, V.: Frustrated chaos in biological networks. Journal of Theoretical Biology 188(2), 187–200 (1997)
Calenbuhr, V., Bersini, H., Stewart, J., Varela, F.J.: Natural tolerance in a simple immune network. Journal of Theoretical Biology 177 (3), 199–213 (1995)
Almeida, C.R., de Abreu, F.V.: Dynamical instabilities lead to sympatric speciation. Evolutionary Ecology Research 5(5), 739–757 (2003)
Cederbom, L., Hall, H., Ivars, F.: CD4(+)CD25(+) regulatory T cells down-regulate co-stimulatory molecules on antigen-presenting cells. European Journal of Immunology 30(6), 1538–1543 (2000)
Wykes, M., Pombo, A., Jenkins, C., MacPherson, G.G.: Dendritic cells interact directly with naive B lymphocytes to transfer antigen and initiate class switching in a primary T-dependent response. Journal of Immunology 161(3), 1313–1319 (1998)
Knight, S.C., Iqball, S., Roberts, M.S., Macatonia, S., Bedford, P.A.: Transfer of antigen between dendritic cells in the stimulation of primary T cell proliferation. European Journal of Immunology 28(5), 1636–1644 (1998)
van Gisbergen, K.P., Sanchez-Hernandez, M., Geijtenbeek, T.B.H., van Kooyk, Y.: Neutrophils mediate immune modulation of dendritic cells through glycosylation-dependent interactions between Mac-1 and DC-SIGN. Journal of Experimental Medicine 201(8), 1281–1292 (2005)
Ferlazzo, G.: Natural killer and dendritic cell liaison: recent insights and open questions. Immunology Letters 101(1), 12–17 (2005)
Zhang, M., et al.: Splenic stroma drives mature dendritic cells to differentiate into regulatory dendritic cells. Nature Immunology 5(11), 1124–1133 (2004)
Hanna, J., et al.: Novel APC-like properties of human NK cells directly regulate T cell activation. Journal of Clinical Investigation 114(11), 1612–1623 (2004)
Mekori, Y.A., Metcalfe, D.D.: Mast cell-T cell interactions. Journal of Allergy and Clinical Immunology 104(3 Pt 1), 517–523 (1999)
Flugel, A., et al.: Neuronal FasL induces cell death of encephalitogenic T lymphocytes. Brain Pathology 10(3), 353–364 (2000)
Thornton, A.M., Shevach, M.E.: CD4(+)CD25(+) immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. Journal of Experimental Medicine 188(2), 287–296 (1998)
Taams, L.S., et al.: Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T cells. Human Immunology 66(3), 222–230 (2005)
Nolte-’t Hoen, E.N., et al.: Uptake of membrane molecules from T cells endows antigen-presenting cells with novel functional properties. European Journal of Immunology 34(11), 3115–3125 (2004)
Taams, L.S., et al.: Anergic T cells actively suppress T cell responses via the antigen-presenting cell. European Journal of Immunology 28(9), 2902–2912 (1998)
Huang, J.F., et al.: TCR-Mediated internalization of peptide-MHC complexes acquired by T cells. Science 286(5441), 952–954 (1999)
Gunzer, M., et al.: Antigen presentation in extracellular matrix: interactions of T cells with dendritic cells are dynamic, short lived, and sequential. Immunity 13(3), 323–332 (2000)
Mempel, T.R., Henrickson, S.E., Von Andrian, U.H.: T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature 427(6970), 154–159 (2004)
Depoil, D., et al.: Immunological synapses are versatile structures enabling selective T cell polarization. Immunity 22(2), 185–194 (2005)
Eissner, G., Kolch, W., Scheurich, P.: Ligands working as receptors: reverse signaling by members of the TNF superfamily enhance the plasticity of the immune system. Cytokine Growth Factor Rev 15, 353–366 (2004)
Lehner, M., et al.: MHC class II antigen signaling induces homotypic and heterotypic cluster formation of human mature monocyte derived dendritic cells in the absence of cell death. Human Immunology 64(8), 762–770 (2003)
Lokshin, A.E., et al.: Differential regulation of maturation and apoptosis of human monocyte-derived dendritic cells mediated by MHC class II. International Immunology 14(9), 1027–1037 (2002)
Walzer, T., et al.: Natural-killer cells and dendritic cells: l’union fait la force. Blood 106(7), 2252–2258 (2005)
Gett, A.V., et al.: T cell fitness determined by signal strength. Nature Immunology 4(4), 355–360 (2003)
Iezzi, G., Karjalainen, K., Lanzavecchia, A.: The duration of antigenic stimulation determines the fate of naive and effector T cells. Immunity 8(1), 89–95 (1998)
Iezzi, G., et al.: The interplay between the duration of TCR and cytokine signaling determines T cell polarization. European Journal Immunology 29(12), 4092–4101 (1999)
Wulfing, C., et al.: Stepwise cytoskeletal polarization as a series of checkpoints in innate but not adaptive cytolytic killing. Proc. Natl. Acad. Sci. U S A 100(13), 7767–7772 (2003)
Davis, D.M.: Assembly of the immunological synapse for T cells and NK cells. Trends in Immunology 23(7), 356–363 (2002)
Davis, D.M., Dustin, M.L.: What is the importance of the immunological synapse? Trends in Immunology 25(6), 323–327 (2004)
Gusfield, D., Irving, R.W.: The stable marriage problem: structure and algorithms. MIT Press, Cambridge (1989)
Mertens, S.: Computational complexity for physicists. Computing in Science and Engineering 4(3), 31–47 (2002)
Hopfield, J.J.: Kinetic proofreading – new mechanism for reducing errors in biosynthetic processes requiring high specificity. Proc. Natl. Acad. Sci. U S A 71(10), 4135–4139 (1974)
Ninio, J.: Kinetic amplification of enzyme discrimination. Biochimie 57(5), 587–595 (1975)
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2006 Springer-Verlag Berlin Heidelberg
About this paper
Cite this paper
Vistulo de Abreu, F., Nolte‘Hoen, E.N.M., Almeida, C.R., Davis, D.M. (2006). Cellular Frustration: A New Conceptual Framework for Understanding Cell-Mediated Immune Responses. In: Bersini, H., Carneiro, J. (eds) Artificial Immune Systems. ICARIS 2006. Lecture Notes in Computer Science, vol 4163. Springer, Berlin, Heidelberg. https://doi.org/10.1007/11823940_4
Download citation
DOI: https://doi.org/10.1007/11823940_4
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-37749-8
Online ISBN: 978-3-540-37751-1
eBook Packages: Computer ScienceComputer Science (R0)