The essential task of a germinal centre reaction is the selection of those B cells that bind the antigen with high affinity.  The exact mechanisms of B cell selection is still unknown and rather difficult to be accessed in experiment.  With the help of an already established agent-based model for the space-time-dynamics of germinal centre reactions [1,2] we compare the most important hypotheses for what the limiting factor for B cell rescue may be.  We discuss competition for antigen sites on follicular dendritic cells, a refractory time for centrocytes after every encounter with follicular dendritic cells, competition for the antigen itself, the role of antigen masking with soluble antibodies, and competition for T cell help.  The unexpected result is that neither competition for interaction sites nor competition for antigen nor antigen masking are in agreement with present experimental data on germinal centre reactions.  We show that these most popular selection mechanisms do not lead to sufficient affinity maturation and do not respect the observed robustness against changes of initial conditions.  However, the best agreement with data was found for the newly hypothesized centrocyte refractory time and for competition for T cell help.  Thus the in silico experiments point towards selection mechanisms that are not in the main focus of current germinal centre research.  Possible experiments to test these hypotheses are proposed

Iber, D.

Maini, P. K.

Meyer-Hermann, M. E.

English

Mathematical Institute Eprints Archive

WORKSHOP B
B Lymphocytes - Development and
Function
1Frankfurt Institute for Advanced Studies (FIAS), Goethe-
University Frankfurt/Main, Frankfurt/Main, Germany and
2Mathematical Institute, Oxford University, Oxford OX1 3LB,
United Kingdom
B.1 Analysis of B cell selection mechanisms in the adaptive
immune response
M. Meyer-Hermann1, P.K. Maini2, and D. Iber2
The essential task of a germinal centre reaction is the selection
of those B cells that bind the antigen with high afﬁnity. The
exact mechanisms of B cell selection is still unknown and
rather difﬁcult to be accessed in experiment. With the help of
an already established agent-based model for the space-time-
dynamics of germinal centre reactions [1,2] we compare the
most important hypotheses for what the limiting factor for B
cell rescue may be. We discuss competition for antigen sites on
follicular dendritic cells, a refractory time for centrocytes after
every encounter with follicular dendritic cells, competition for
the antigen itself, the role of antigen masking with soluble
antibodies, and competition for T cell help. The unexpected
result is that neither competition for interaction sites nor
competition for antigen nor antigen masking are in agreement
with present experimental data on germinal centre reactions.
We show that these most popular selection mechanisms do not
lead to sufﬁcient afﬁnity maturation and do not respect the
observed robustness against changes of initial conditions.
However, the best agreement with data was found for the
newly hypothesized centrocyte refractory time and for
competition for T cell help. Thus the in silico experiments
point towards selection mechanisms that are not in the main
focus of current germinal centre research. Possible experiments
to test these hypotheses are proposed.
References:
[1] Meyer-Hermann, M., A mathematical model for the
germinal center morphology and afﬁnity maturation. J.
Theor. Biol. 216 (2002) 273–300.
[2] Meyer-Hermann, M., Maini, P.K., Back to ‘‘one-way’’
germinal centers. J. Immunol. 174 (2005) 2489–2493.
Institute of Immunology, Otto-von-Guericke University,
Magdeburg, Germany
B.2 Analysis of the functional redundancy among the non-raft
transmembrane adaptor proteins LAX, SIT and TRIM.
B. Arndt, B. Schraven, and L. Simeoni
To date, 7 Transmembrane Adaptor Proteins (TRAP) have
been identiﬁed: LAT; LAX, LIME, NTAL, PAG, SIT and
TRIM. Among them, LAX, SIT and TRIM are localised in
the non-raft fraction of the plasma membrane and may
function as negative regulators of antigen receptor-mediated
signalling. In fact, analysis of LAX-deﬁcient mice revealed that
LAX inhibits TCR- and BCR-mediated signalling pathways.
Similarly, SIT functions as a negative regulator of signals
transduced through the TCR and is required to set the
threshold for thymocyte selection and peripheral T-cell
activation. Conversely to LAX and SIT, TRIM appears to
be dispensable for normal T-cell development and T-cell
function as TRIM/ mice show no obvious defects.
Although the data from knock-out models indicate that the
non-raft-associated TRAPs LAX and SIT are required for
proper lymphocyte function, their effects on the immune
system are rather mild or even absent as in TRIM-deﬁcient
mice. This could suggest that non-raft TRAPs share a
functional redundancy in lymphocytes.
While LAX/TRIM double deﬁcient mice are still under
investigation, analysis of SIT/TRIM-deﬁcient mice revealed
that these two adapters indeed share redundant functions
during thymic selection and mutations in their genes could
alter immune tolerance and lead to the generation/activation
of autoreactive T cells.
Surprisingly, SIT/LAX double deﬁcient mice show increased
proportions of B1 B-cells in the peritoneal cavity and in the
spleen, thus indicating that SIT and LAX together regulate the
expansion of this particular B-cell subset that has been
associated with autoimmune diseases. Conversely to their
crucial role in B1 B-cells, LAX and SIT seem not to be
redundant for T-cell and conventional B2-cell development
and function.
In summary, our data show that non-raft TRAPs play
important but redundant roles in ﬁnely tuning immune
responses. Moreover they also share overlapping functions,
by acting as negative regulators, in controlling the develop-
ment/expansion of distinct lymphocyte subpopulations and in
maintaining tolerance.
Immunregulation, Deutsches Rheuma Forschungszentrum,
Berlin, Germany
B.3 B cells activated through TLR produce high amounts of
Interleukin-10
T. Roch, K. Hoehlig, V. Lampropoulou, and S. Fillatreau
Interleukin-10 producing B cells can suppress inﬂammatory
immune responses despite persistence of a microbial stimulus.
The signals controlling IL-10 production by B cells remain to
be determined. Here, we show that only engagement of Toll-
Like Receptors (TLRs), but not the two other major pathways
involved in B cell activation (B cell receptor and CD40),
stimulates B cells to produce high amounts of IL-10. The
secretion of IL-10 induced by TLR-signals is strongly
diminished when CD40 is concomitantly stimulated. Instead
of IL-10, B cells co-stimulated through CD40 and TLRs
secrete IL-6. This indicates that T cells control which cytokines
are produced by TLR-activated B cells. The secretion of IL-10
by LPS- and CpG-stimulated B cells requires MyD88. The
genetic background controls the amount of IL-10 produced: B
cells from BALB/c mice secrete around 10 fold more IL-10
than their C57BL/6 counterparts.
ARTICLE IN PRESS
Joint Annual Meeting of the German and Scandinavian Societies of Immunology / Immunobiology 210 (2005) 361–622372


Analysis of the functional redundancy among the non-raft transmembrane adaptor proteins

Analysis of B cell selection mechanisms in the adaptive immune response

Oxford University Research Archive

WORKSHOP BB Lymphocytes - Development andFunction1Frankfurt Institute for Advanced Studies (FIAS), Goethe-University Frankfurt/Main, Frankfurt/Main, Germany and2Mathematical Institute, Oxford University, Oxford OX1 3LB,United KingdomB.1 Analysis of B cell selection mechanisms in the adaptiveimmune responseM. Meyer-Hermann1, P.K. Maini2, and D. Iber2The essential task of a germinal centre reaction is the selectionof those B cells that bind the antigen with high affinity. Theexact mechanisms of B cell selection is still unknown andrather difficult to be accessed in experiment. With the help ofan already established agent-based model for the space-time-dynamics of germinal centre reactions [1,2] we compare themost important hypotheses for what the limiting factor for Bcell rescue may be. We discuss competition for antigen sites onfollicular dendritic cells, a refractory time for centrocytes afterevery encounter with follicular dendritic cells, competition forthe antigen itself, the role of antigen masking with solubleantibodies, and competition for T cell help. The unexpectedresult is that neither competition for interaction sites norcompetition for antigen nor antigen masking are in agreementwith present experimental data on germinal centre reactions.We show that these most popular selection mechanisms do notlead to sufficient affinity maturation and do not respect theobserved robustness against changes of initial conditions.However, the best agreement with data was found for thenewly hypothesized centrocyte refractory time and forcompetition for T cell help. Thus the in silico experimentspoint towards selection mechanisms that are not in the mainfocus of current germinal centre research. Possible experimentsto test these hypotheses are proposed.References:[1] Meyer-Hermann, M., A mathematical model for thegerminal center morphology and affinity maturation. J.Theor. Biol. 216 (2002) 273–300.[2] Meyer-Hermann, M., Maini, P.K., Back to ‘‘one-way’’germinal centers. J. Immunol. 174 (2005) 2489–2493.Institute of Immunology, Otto-von-Guericke University,Magdeburg, GermanyB.2 Analysis of the functional redundancy among the non-rafttransmembrane adaptor proteins LAX, SIT and TRIM.B. Arndt, B. Schraven, and L. SimeoniTo date, 7 Transmembrane Adaptor Proteins (TRAP) havebeen identified: LAT; LAX, LIME, NTAL, PAG, SIT andTRIM. Among them, LAX, SIT and TRIM are localised inthe non-raft fraction of the plasma membrane and mayfunction as negative regulators of antigen receptor-mediatedsignalling. In fact, analysis of LAX-deficient mice revealed thatLAX inhibits TCR- and BCR-mediated signalling pathways.Similarly, SIT functions as a negative regulator of signalstransduced through the TCR and is required to set thethreshold for thymocyte selection and peripheral T-cellactivation. Conversely to LAX and SIT, TRIM appears tobe dispensable for normal T-cell development and T-cellfunction as TRIM/ mice show no obvious defects.Although the data from knock-out models indicate that thenon-raft-associated TRAPs LAX and SIT are required forproper lymphocyte function, their effects on the immunesystem are rather mild or even absent as in TRIM-deficientmice. This could suggest that non-raft TRAPs share afunctional redundancy in lymphocytes.While LAX/TRIM double deficient mice are still underinvestigation, analysis of SIT/TRIM-deficient mice revealedthat these two adapters indeed share redundant functionsduring thymic selection and mutations in their genes couldalter immune tolerance and lead to the generation/activationof autoreactive T cells.Surprisingly, SIT/LAX double deficient mice show increasedproportions of B1 B-cells in the peritoneal cavity and in thespleen, thus indicating that SIT and LAX together regulate theexpansion of this particular B-cell subset that has beenassociated with autoimmune diseases. Conversely to theircrucial role in B1 B-cells, LAX and SIT seem not to beredundant for T-cell and conventional B2-cell developmentand function.In summary, our data show that non-raft TRAPs playimportant but redundant roles in finely tuning immuneresponses. Moreover they also share overlapping functions,by acting as negative regulators, in controlling the develop-ment/expansion of distinct lymphocyte subpopulations and inmaintaining tolerance.Immunregulation, Deutsches Rheuma Forschungszentrum,Berlin, GermanyB.3 B cells activated through TLR produce high amounts ofInterleukin-10T. Roch, K. Hoehlig, V. Lampropoulou, and S. FillatreauInterleukin-10 producing B cells can suppress inflammatoryimmune responses despite persistence of a microbial stimulus.The signals controlling IL-10 production by B cells remain tobe determined. Here, we show that only engagement of Toll-Like Receptors (TLRs), but not the two other major pathwaysinvolved in B cell activation (B cell receptor and CD40),stimulates B cells to produce high amounts of IL-10. Thesecretion of IL-10 induced by TLR-signals is stronglydiminished when CD40 is concomitantly stimulated. Insteadof IL-10, B cells co-stimulated through CD40 and TLRssecrete IL-6. This indicates that T cells control which cytokinesare produced by TLR-activated B cells. The secretion of IL-10by LPS- and CpG-stimulated B cells requires MyD88. Thegenetic background controls the amount of IL-10 produced: Bcells from BALB/c mice secrete around 10 fold more IL-10than their C57BL/6 counterparts.ARTICLE IN PRESSJoint Annual Meeting of the German and Scandinavian Societies of Immunology / Immunobiology 210 (2005) 361–622372

Analysis of B cell selection mechanisms in the adaptive immune response

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