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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