Autonomous activation of B and T cells in antigen‐free mice

Pereira, Pablo; Forni, Luciana; Larsson, Eva‐Lotta; Cooper, Max D.; Heusser, Christoph; Coutinho, António

doi:10.1002/eji.1830160616

Cited by 179 publications

(105 citation statements)

References 22 publications

(16 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We speculate that these results account for the differences reported to exist between highly connected neonatal networks (Holmberg et al, 1984(Holmberg et al, , 1986Vakil and Kearny, 1986) and weakly connected adult networks (Pollok et al, 1982;Holmberg et al, 1986). The former do indeed display autonomous activity (Pereira et al, 1986). We have demonstrated here that this marked difference an be accounted for solely by the (possibly gradual) difference in the connectance of the two types of networks.…”

Section: B: [] )supporting

confidence: 64%

Unreasonable implications of reasonable idiotypic network assumptions

Boer

Hogeweg

1989

Bltn Mathcal Biology

View full text Add to dashboard Cite

We first analyse a simple symmetric model of the idiotypic network. In the model idiotypic interactions regulate B cell proliferation. Three non-idiotypic processes are incorporated: (1) influx of newborn cells; (2) turnover of cells; (3) antigen. Antigen also regulates proliferation.A model of 2 B cell populations has 3 stable equilibria: one virgin, two immune. The twodimensional system thus remembers antigens, i.e. accounts for immunity. By contrast, if an idiotypic clone proliferates (in response to antigen), its anti-idiotypic partner is unable to control this. Symmetric idiotypic networks thus fail to account for proliferation regulation.In high-D networks we run into two problems. Firstly, if the network accounts for memory, idiotypic activation always propagates very deeply into the network. This is very unrealistic, but is an implication of the"realistic" assumption that it should be easier to activate all cells of a small virgin clone than to maintain the activation of all cells of a large (immune) clone. Secondly, graph theory teaches us that if the (random) network connectance exceeds a threshold level of one interaction per clone, most clones are interconnected. We show that this theory is also applicable to immune networks based on complementary matching idiotypes. The combination of the first "percolation" result with the "interconnectance" result means that the first stimulation of the network with antigen should eventually affect most of the clones. We think this is unreasonable.Another threshold property of the network connectivity is the existence of a virgin state. A gradual increase in network connectance eliminates the virgin state and thus causes an abrupt change in network behaviour. In contrast to weakly connected systems, highly connected networks display autonomous activity and are unresponsive to external antigens. Similar differences between neonatal and adult networks have been described by experimentalists.The robustness of these results is tested with a network in which idiotypic inactivation of a clone occurs more generally than activation. Such "long-range inhibition" is known to promote pattern formation. However, in our model it fails to reduce the percolation, and additionally, generates semi-chaotic behaviour. In our network, the inhibition of a clone that is inhibiting can alter this clone into a clone that is activating. Hence "long-range inhibition" implies "long-range activation", and idiotypic activation fails to remain localized.We next complicate this model by incorporating antibody production. Although this "antibody" model statically accounts for the same set of equilibrium points, it dynamically fails to account for state switching (i.e. memory). The switching behaviour is disturbed by the autonomous slow decay of the (long-lived) antibodies. After antigenic triggering the system now performs complex cyclic behaviour. Finally, it is suggested that (idiotypic) formation of antibody complexes can play only a secondary role in the network.In conclusion, our results ca...

show abstract

Section: B: [] )supporting

confidence: 64%

Unreasonable implications of reasonable idiotypic network assumptions

Boer

Hogeweg

1989

Bltn Mathcal Biology

View full text Add to dashboard Cite

show abstract

“…A formal demonstration of the absence of exogenous Ag stimulation in GF mice is difficult to provide. One should note, however, that GF mice have similar numbers of activated splenic T cells as compared with SPF animals (22), whereas a 100 -200-fold reduction in the number of T cells in the gut-associated lymphoid tissue is observed. If exogenous Ags were responsible for such natural activation, a similar reduction in the number of activated splenic T cells would be expected.…”

Section: Discussionmentioning

confidence: 89%

“…Mice kept under GF and Ag-free conditions contain almost normal numbers of naturally activated T and B cells in the spleen, including functionally differentiated effector cells (22).…”

Section: Cd45rb Low Cd4 T Cells Of Gf Mice Control Naive Cd4 T Cellinmentioning

confidence: 99%

Regulatory CD4 T Cells Control the Size of the Peripheral Activated/Memory CD4 T Cell Compartment

Annacker

Burlen-Defranoux

Pimenta-Araujo

et al. 2000

The Journal of Immunology

136

View full text Add to dashboard Cite

The mechanisms leading to stable T cell numbers in the periphery of a healthy animal are, to date, not well understood. We followed the expansion of CD45RBhigh (naive) and CD45RBlow (activated/memory) CD4 T cells transferred from normal mice into syngeneic Rag-20/0 recipients and the dynamics of peripheral reconstitution when both populations were coinjected. Naive cells acquired an activated phenotype and showed a high proliferative capacity that was dependent on the environment in which the recipients were kept (specific pathogen-free vs conventional housing conditions), the age of the recipients, and the presence of CD45RBlow T cells in the injected cohort. CD45RBlow CD4 T cells protected the host from CD45RBhigh CD4 T cell-induced inflammatory bowel disease and showed a limited degree of expansion. CD45RBlow CD4 T cells isolated from GF mice also showed the ability to prevent inflammatory bowel disease, indicating that at least part of the natural regulatory T cells are self-reactive. The results indicate that 1) peripheral T cell expansion in lymphocyte-deficient recipients represent classical immune responses, which are mainly promoted by exogenous Ags and 2) natural regulatory T cells control the size of the activated/memory peripheral CD4 T cell compartment.

show abstract

“…Selftolerance in normal individuals is likely to be, at least in part, achieved by similar mechanisms. Thus, normal and antigenfree mice contain high numbers of activated B and T cells (33,34). Importantly, CD8' blasts isolated from normal mice are efficient suppressors of B-cell response but lack cytotoxic ability, while helper cells but not inflammatory CD4' cells are naturally activated.…”

Section: Resultsmentioning

confidence: 99%