The main scientific objective of the Lymphocyte Population Biology Unit are:
To study the mechanisms of homeostasis,
which control the number of B and T lymphocytes.
To study the role of cellular competition in lymphocyte selection and immune
responses.
To study the mechanisms of immunological memory persistence.
In 2009 we followed several lines of research:
1- Bystander CD4+ T cell help to
CD8+ T cells during lymphopenia driven proliferation (LDP).
We studied the fate of selected populations of CD8+ and CD4+ T cells in T
cell deficient CD3ε-/- mice. We found that the reconstitution of the CD8+
T cell pool is independent of the nature of the CD8+ T cells transferred,
suggesting that the resulting pools are environmentally controlled. However,
co-transfer of CD8 T cells with CD4+ T cells modifies CD8+ T cell recovery
- results in the dramatic increase of the CD8+ T cell numbers recovered.
This “helper” effect generates preferentially an increased number of CD8
T cells expressing a TEM phenotype and cytotoxic effector molecules and is
does not alter the number of cells with a TCM phenotype. We showed that during
LDP bystander CD4 T cell help did not involve CD40 expression by the expanding
CD8 T cells, but required CD40 expression by host non-lymphoid cells. Using
cells from mice invalidated for the CCR5 molecule we showed that the helper
effects also require close vicinity between the interacting CD4 and CD8 T
cells. Moreover the bystander helper effects were dependent on IL-2 produced
by the expanding CD4+ T cells and required expression of IL-2Rb chain but
not of the IL-2Ra chain by the responding CD8+ T cells. Thus, plasticity
on the TEM-phenotype CD8+ T cell niche contrasts with stringent homeostatic
mechanisms in TCM-phenotype CD8+ T cell numbers and points todifferent homeostatic
control mechanisms for TCM and TEM-phenotype CD8+ T cells.
2. Selection and control of IgM-secreting
cells.
We studied the fate of mature lymph node (LN) B cells injected into
immune-deficient Rag° hosts. We found that a fraction of the transferred
population of LN B cells expanded and persisted for prolonged periods of
time. A significant fraction of the surviving B cells express an activated
MZ B cell phenotype and were actively engaged in IgM-secretion. Serum IgM
concentrations identical to those of control mice were readily reached in
the presence of a reduced number of B cells. We investigated different aspects
of the biology of the natural IgM-secreting cells. We found that mechanisms
of feedback regulation control the number of activated B cells. We have found
that the IgG produced by the first B cell population controls the production
of IgM by the second B cell populations. Mouse IgG passively administered
into Rag-deficient hosts strongly inhibits the activation and IgM production
by adoptively transferred B cells. More recently, we found that B cells from
FcγRIIB-/- donors are not suppressed. These findings suggest that the number
of activated IgM-secreting cells may be controlled by quorum-sensing mechanisms
and that when the serum Ig levels reach a determined threshold, these “signals”
are captured by receptors at the B cell surface that inhibit B cell activation.
3- The homeostasis of the IL-2 producing
T cells.
We have shown that the interactions between the CD4+CD25+ regulatory T cells
and naïve CD25-CD4+ T cells are of major relevance for the establishment
of peripheral CD4 T cell homeostasis. We demonstrated that the IL-2Ra is
an absolute requirement for the generation of the regulatory cells. The expression
of the high-affinity IL-2Ra endows these cells with the capacity to explore
the IL-2 resource, which ensures their peripheral survival, while keeping
their number tied to the number of CD4+ T cells that produce IL-2. The indexing
of CD4+CD25+Foxp3+ Treg cells to the number of activated IL-2-producing CD4+
T cells may constitute a feedback mechanism that controls T cell expansion
during immune responses, thus preventing autoimmune or lymphoproliferative
diseases. These results indicated that the number of IL-2-producing cells
is relevant for regulatory T cells homeostasis as they may control their
maintenance in the peripheral pools. These findings indicate that a quorum-sensing
feedback loop, where the IL-2 produced by T cell sub-population is detected
by a sub-population of CD4 Treg cells expressing the high-affinity IL-2Ra-chain
that controls the number of total CD4 T cells. That is to say: overall CD4
T cell populations adapt their behavior according to the detection of the
quantities of IL-2 produced. We are currently investigating The properties
and homeostasis of IL-2 producing (IL-2p) T cells.
Keywords: lymphocyte homeostasis / immunological memory / regulatory T cells
The main scientific objectives of the Lymphocyte Population Biology Unit are:
To study the mechanisms of homeostasis, which control the number of B and T lymphocytes.
To study the dynamics of the lymphocyte populations: rates of cell production and cell death, mechanisms of lymphocyte survival.
To study the role of cellular competition in lymphocyte selection and immune responses.
To study the mechanisms of immunological memory persistence.
To investigate these different issues we have followed several lines of research during 2008:
1- Bystander CD4+ T cell help to
CD8+ T cells during lymphopenia driven proliferation (LDP).
Since a fully functioning immune system requires a variety of lymphocyte
sub-sets, lymphpocyte homeostasis should control both absolute numbers
and relative sizes of each sub-population; otherwise, deregulation and disease
may occur. We studied CD8:CD4 T cell interactions during LDP. We found that
the co-transfer of CD8+ T cells sub-sets with naïve CD4+ cells results
in the 10-fold increase of the number of CD8+ T cells recovered irrespectively
of the CD8 T cell sub-set transferred. This “bystander helper” effect
results in the preferential accumulation of cells with a TEM phenotype. The
mechanisms that mediate the CD4 bystander helper require close vicinity between
the interacting CD4 and CD8 T cells.
2. Selection and control of IgM-secreting
cells.
We studied the fate of mature lymph node (LN) B cells injected into immune-deficient
hosts unable to produce B cells. Using this experimental model we found that
there are mechanisms of feedback regulation controlling the total number
of activated B cells and B cell terminal differentiation. We have found that
the IgG produced by the first B cell population controls the production of
IgM by the second B cell population. Our findings suggest that the number
of activated IgM-secreting B cells may be controlled by quorum-sensing mechanisms:
when Ig levels reach a certain threshold, these “signals” are
captured by receptors at the B cell surface that inhibit new B cell activation.
3- Endogenous TCR recombination in
TCR transgenic Rag-2 deficient mice.
The transfer of monoclonal TCR Tg T cells from Rag-2-/- mice, into allogenic
Rag-/-gc-/- hosts results in the accumulation in the host mice of donor T
cells expressing non-Tg TCRs. Molecular analysis of the expressed TCRs confirmed
that these donor T cells expressed a broad diversity of recombined endogenous
TCRs. Nucleotide sequence analysis indicates that we are in presence of a “classical” Rag-dependent
recombination in spite of the Rag-deficiency of the donors. We found that
the T cells expressing non-transgenic TCRs pre-exist in a very limited number
both in the thymus and at the periphery of the donor Rag-2-/- mice.
Key words : lymphocyte homeostasis / immunological memory / regulatory T cells
The main scientific objectives of the Lymphocyte Population Biology Unit are:
To investigate these different issues we have followed several lines of research. We summarize our most important observations during 2007:
1- Endogenous TCR recombination in TCR transgenic Rag-2 deficient mice. The transfer of monoclonal TCR Tg T cells from H2k 5CC7 Rag-2-/- mice, which are specific for the pigeon cytochrome C, into allogenic H2b Rag-/-gc-/- hosts resulted in the accumulation in the host mice of donor T cells expressing non-Tg TCRs. Molecular analysis of the expressed TCRs by Immunoscope confirmed that these donor T cells expressed a broad diversity of recombined endogenous TCRs. Nucleotide sequence analysis of the expressed non-Tg TCR indicates that we are in presence of a mechanism of “classical” Rag-dependent recombination in spite of the Rag-2 deficiency of the 5CC7 donors. We found that T cells expressing a non-transgenic TCR pre-exist in a very limited number both in the thymus and at the periphery of the naive 5CC7 Rag-2-/- mice. These results have important implications for the studies using TCR Rag-/- transgenic mice.
2- TCR specificity and clonal competition. We asked to which extend TCR specificity determines clonal competition for proliferation and/or survival during lymphopenia driven proliferation (LDP). We found that resident monoclonal T cells in TCR Tg Rag-/- mice, or monoclonal LDP derived TCR Tg T cells in Rag-/- hosts, inhibit the survival and/or the proliferation of T cells presenting the same TCR, but not of TCR Tg T cells bearing a different specificity. Using different transfer approaches we extended this notion to polyclonal T cells. Our findings show that T TCR-specificity determines peripheral T cell fate and indicate that specific sp-MHC complexes are limiting resources shared between developing, surviving and proliferating T cells.
3- Bystander CD4+ T cell help to CD8+ T cells during lymphopenia driven proliferation (LDP). Since a fully functioning immune system requires a variety of lymphocyte sub-sets, lymphpocyte homeostasis should control both absolute numbers and relative sizes of each sub-population; otherwise, deregulation and disease may occur. We studied CD8:CD4 T cell interactions during LDP. We found that the co-transfer of CD8+ T cells sub-sets with naïve CD4+ cells results in the 10-fold increase of the number of CD8+ T cells recovered irrespectively of the CD8 T cell sub-set transferred. This “bystander helper” effect results in the preferential accumulation of cells with a TEM phenotype. The mechanisms that mediate the CD4 bystander helper effect are currently under investigation.
Keywords: lymphocyte homeostasis / immunological memory / regulatory T cells
The main scientific objectives of the Lymphocyte Population Biology Unit are:
To investigate these different issues we have followed several lines of research. We summarize our most important observations during 2006: Agonist driven development of CD4+CD25+Foxp3+ regulatory T
cells requires a second signal mediated by Stat6. (V. Sanchez-Guajardo,
S. Garcia & A. Freitas) Endogenous TCR recombination in TCR transgenic Rag-2 deficient
mice (C. Montaudouin, S. Garcia & A. Freitas) TCR specificity and clonal competition (C.
Leitao, A. Freitas & S. Garcia) Bystander CD4+ T cell help to CD8+ T cells during lymphopenia
driven proliferation (LDP) (B. Zaragoza & A. Freitas) The Bw cells, a novel B cell population conserved in the whole
genus Mus (A. Thiriot & D. Rueff-Juy) Keywords: B cells / T cells / lymphocyte homeostasis / lymphocyte survival / immunological memory The research objectives of the « UBPL» are: B cell homeostasis and selection of IgM-secreting cells
(Yi Hao). Toll-like Receptor 9 controls key checkpoints of B lymphocyte
development (Yi Hao). CD8 T cell survival (Yi Hao). Role of the MHC-ligand/TCR interactions in the survival and
LDO of CD8 T cells (Sylvie Garcia). Differential role of STAT proteins in the selection of antigen-specific
of CD4+ T cells (Vanesa Guajardo). Competition and survival among memory T cells (Catarina Leitao,
Sylvie Garcia). Keywords : B cells, T cells, lymphocyte homeostasis, lymphocyte survival, immunological memory
Last update : October 1st, 2012 |