Connexin 43 Signaling Enhances the Generation of Foxp3+ Regulatory T Cells (original) (raw)
Related papers
The Journal of Immunology, 2009
Homeostasis in the immune system is maintained by specialized regulatory CD4 ؉ T cells (T reg) expressing transcription factor Foxp3. According to the current paradigm, high-affinity interactions between TCRs and class II MHC-peptide complexes in thymus "instruct" developing thymocytes to up-regulate Foxp3 and become T reg cells. However, the loss or down-regulation of Foxp3 does not disrupt the development of T reg cells but abrogates their suppressor function. In this study, we show that Foxp3-deficient T reg cells in scurfy mice harboring a null mutation of the Foxp3 gene retained cellular features of T reg cells including in vitro anergy, impaired production of inflammatory cytokines, and dependence on exogenous IL-2 for proliferation and homeostatic expansion. Foxp3-deficient T reg cells expressed a low level of activation markers, did not expand relative to other CD4 ؉ T cells, and produced IL-4 and immunomodulatory cytokines IL-10 and TGF- when stimulated. Global gene expression profiling revealed significant similarities between T reg cells expressing and lacking Foxp3. These results argue that Foxp3 deficiency alone does not convert T reg cells into conventional effector CD4 ؉ T cells but rather these cells constitute a distinct cell subset with unique features.
A model system to study Connexin 43 in the immune system
Molecular Immunology, 2009
Connexin 43 (Cx43) is the predominant gap junction protein expressed in immune cells. Previous manuscripts have stated that gap junctions may play a role in antigen cross-presentation, dendritic cell maturation, T cell development, and regulatory T cell function. Many of these previous studies were performed in vitro. In vivo studies were not directly possible in adult mice because Cx43−/− mice die shortly after birth due to a cardiac malformation. To overcome these drawbacks, we have developed a mouse model that deletes Cx43 in the immune system while maintaining normal cardiac function. In our model, irradiated CD45.1+ wild-type mice were reconstituted with Cx43WT, Cx43±, or Cx43−/− hematopoietic fetal liver cells that were derived from CD45.2+ mice. The presence of CD45.2 allowed us to identify and track the donor cells following reconstitution. We determined that Cx43± and Cx43−/− hematopoietic cells were able to reconstitute irradiated mice as well as Cx43WT cells. Reconstitution was nearly 100% in the thymus and over 90% in the spleen. There appeared to be no difference in thymocyte development or in the ability of lymphocytes to transmigrate to peripheral lymphoid organs. However in response to inflammation, Cx43± radiation chimeras had increased peritoneal infiltration compared to Cx43WT and Cx43−/− groups. IgG responses were normal in all groups but the Cx43−/− reconstituted mice had an elevated IgM response. Our data suggests that Cx43 may not be involved in the normal development of the immune system but may regulate certain effector functions in vivo.
Journal of immunology (Baltimore, Md. : 1950), 2017
Accumulating evidence suggests that Foxp3(+) cells can downregulate the expression of Foxp3, but whether thymically derived regulatory T cells (tTregs; especially committed tTregs) are capable of downregulating Foxp3 expression and being reprogrammed into other T effector cells remains controversial. Using a novel tTreg lineage-tracing mouse line, we were able to label epigenetically stable Foxp3(+) cells derived from the thymus and demonstrate that mature tTregs are stable under homeostatic conditions. However, TCR engagement and sequential functional specialization of tTregs led to the generation of Foxp3 instability and reprogramming into the Th lineage. We further demonstrated that the signal switch from IL-2 to ICOS during Treg activation induced Treg instability and reprogramming. By using a dual lineage tracing model, we demonstrated that effector Tregs can revert to central Tregs, and this reversion is associated with increasing Foxp3 stability in vivo.
The Foxp3+ regulatory T cell: a jack of all trades, master of regulation
Nature Immunology, 2008
The function of regulatory T cells (T reg cells) has been attributed to a growing number of diverse pathways, molecules and processes. Seemingly contradictory conclusions regarding the mechanisms underlying T reg cell suppressive activity have revitalized skeptics in the field who challenge the core validity of the idea of T reg cells as central immune regulators. However, we note that a consensus may be emerging from the data: that multiple T reg cell functions act either directly or indirectly at the site of antigen presentation to create a regulatory milieu that promotes bystander suppression and infectious tolerance. Thus, the versatility and adaptability of the Foxp3 + T reg cells may in fact be the best argument that these cells are 'multitalented masters of immune regulation'.
Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells
International Immunology, 2004
Naturally occurring CD25 1 CD4 1 regulatory T cells are engaged in the maintenance of immunological self-tolerance and down-regulation of various immune responses. Recent studies with mice showed that Foxp3, which encodes the transcription factor Scurfin, is a master regulatory gene for the development and function of CD25 1 CD4 1 regulatory T cells. Here we examined the role of FOXP3 in human CD25 1 CD4 1 regulatory T cells. The FOXP3 gene and its protein product were preferentially expressed in peripheral CD25 1 CD4 1 T cells, in particular CD25 1 CD45RO 1 CD4 1 T cells in normal individuals and, interestingly, in some human T cell leukemia virus type 1-infected T cell lines, which constitutively express CD25. TCR stimulation of CD25 ÿ CD45RO ÿ CD4 1 naive T cells failed to elicit FOXP3 expression at the gene or protein level. Ex vivo retroviral gene transfer of FOXP3, on the other hand, converted peripheral CD25 ÿ CD45RO ÿ CD4 1 naive T cells into a regulatory T cell phenotype similar to CD25 1 CD4 1 regulatory T cells. For example, FOXP3-transduced T cells exhibited impaired proliferation and production of cytokines including IL-2 and IL-10 upon TCR stimulation, up-regulated the expression of regulatory T cell-associated molecules such as CD25 and CTL-associated antigen-4 and suppressed in vitro proliferation of other T cells in a cell-cell contact-dependent manner. Thus, human FOXP3 is a crucial regulatory gene for the development and function of CD25 1 CD4 1 regulatory T cells, and can be used as their reliable marker. Furthermore, regulatory T cells de novo produced from normal naive T cells by FOXP3 transduction can be instrumental for treatment of autoimmune/ inflammatory diseases and negative control of various immune responses.