| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Germinal Center Prostaglandins
|
10%) of T cells in the light zone of the germinal center does not undergo proliferation and is insensitive to activation-induced cell death (AICD) despite continued antigenic exposure. Lee et al. (p. 1390
), who previously reported that human FDC expressed PGI synthase (PGIS), hypothesized that FDC may control T cell function in the germinal center through a PG-dependent mechanism. Using human tonsil tissue and a human FDC cell line (HK), the authors found that FDC expressed PGE synthase (PGES) as well as PGIS. Exposure to TNF-
, TGF-β, and LPS increased COX-2 and PGES levels, while PGIS and COX-1 expression was constitutive. Increases in enzyme expression directly correlated with enhanced PGE2 and PGI2 production and were blocked by treatment with both indomethacin and a specific COX-2 inhibitor. Coculture experiments showed that HK cells suppressed T cell proliferation and AICD, as did treatment of the T cells with PGI2 and PGE2. The authors concluded that FDC use PG to protect germinal center T cells from AICD at a time of considerable antigenic challenge and that the use of anti-inflammatory drugs that inhibit PG production during vaccination or infection may disturb this delicate balance. Colonic Cross-Talk
There is significant evidence that the mucosal and systemic immune compartments communicate despite structural and functional independence. However, the mechanism by which this occurs is still unclear. Chang et al. (p. 1609
) used an elegant model of vaccinating mice subcutaneously (SC) with tetanus toxoid (TT) and the adjuvant cholera toxin followed by an intrarectal (IR) boost of the same. They found that priming both the systemic and mucosal systems led to an increase in the number of Ag-specific IgA Ab-secreting cells (ASC) expressing CXCR4 and CCR10 in the large intestine. When only mucosal immunization was used, IgA ASC expressed only CCR10, indicating that the CXCR4+CCR10+ ASC found after SC-IR immunization are of systemic origin. TT-specific IgA was also found in vaginal, nasal, salivary, and fecal samples after the SC-IR regimen. Mice depleted of colonic patches (CP) by in utero treatment of anti-IL-7R had no IgA ASC in the large intestine after SC-IR immunization, and the authors found the CP to be the major site of IgA isotype switching after SC-IR immunization. The generation of Ag-specific IgA ASC in the large intestine after SC-IR immunization was comparable between wild-type and TLR2–/–, TLR4–/–, MyD88–/–, and TRIF–/– mice, showing that the mechanism of IgA ASC generation was independent of the innate immune system. This study demonstrates that a specific pathway of immune cross-talk between the systemic and mucosal immune system exists in the colon independent of innate immunity.
Notch License to Regulate
Mesenchymal stem cells (MSC), a small portion of the bone marrow cellular population, have been shown to be potent inhibitors of T cell responses. In some cases, haplo-identical MSC have been infused to treat acute and otherwise refractory graft vs host disease (GVHD). Li et al. (p. 1598 ) investigated the effect of adult MSC on CD34+ myeloid dendritic cells (DC). They found that MSC inhibited the differentiation of adult CD34+ hemopoietic progenitor cells into interstitial and Langerhans cell DC as determined by surface marker expression. The effects of the MSC were most potent in direct cell contact conditions, and the MSC-DC created in these conditions were considered to have a regulatory phenotype because they expressed high IL-10 and low IL-12, inhibited the proliferation of alloreactive T cells in an MLR assay, and induced the generation of alloantigen-specific T regulatory cells (Tregs) expressing TGF-β and FoxP3. Despite the MSC-DC expression of IL-10, the creation of the Tregs was independent of this cytokine as anti-IL-10 blocking treatment had no effect. MSC cell:cell contact with DC activated the Notch pathway and increased Hes1 expression in the MSC-DC. These results present an explanation for how MSC direct the fate of DC into regulatory cells that can suppress T cell responses.
Protection against a Pandemic?
|
, IFN-
, IL-5, and IL-13 were within the CD45RA– population, suggesting that these were memory cells that had been generated against different influenza viruses. Taken together, these data show that most healthy individuals may already have some protection against the H5N1 virus and that vaccination with other viruses such as H1N1 and H3N2 can increase this immunity. Are LatY136F Mice Truly Autoimmune?
|
Sweet CD99
Paired Ig-like type 2 receptors (PILR), found on murine NK cells, macrophages, and dendritic cells, have an inhibitory isoform, PILR, and an activating isoform, PILRβ. NK cell cytotoxicity of target cells expressing CD99 is mediated by PILRβ. Wang et al. (p. 1686
) have demonstrated that PILR recognition of CD99 is dependent on the addition of sialylated O-linked sugar chains at particular threonines. Point mutations revealed that the activating PILRβ required O-glycosylation at threonines 45 and 50, while the inhibitory PILR required the correct glycosylation at only one residue. When sialic acid was removed from CD99 by neuraminidase treatment, the molecular weight was reduced and PILR binding abrogated. Additional experiments demonstrated that the presence of core-2 glycans on CD99 inhibited PILR recognition and that complete O-glycosylation of CD99 is necessary for NK cell PILRβ-mediated cytotoxicity. Thus, the addition of specific carbohydrates mediates the function of these Ig superfamily receptors.
T Cells SIT
The T cell transmembrane adaptor protein SIT negatively regulates TCR signaling and affects selection in the thymus by setting TCR activation thresholds and controlling the expression of CD5. To examine the role of SIT in maintaining T cell peripheral homeostasis, Posevitz et al. (p. 1634 ) used SIT-deficient mice. They observed that SIT–/– mice have an accumulation of CD44highCD8+ T cells, indicating a memory-like population that was preferentially expanded, and a decrease in the number of naive CD8+ T cells. Adoptive transfer experiments demonstrated that loss of SIT lowers the TCR activation threshold and increases homeostatic proliferation of CD8+ T cells. SIT–/– mice also had lower peripheral T cell expression of the CD8 coreceptor when compared with wild-type mice. Because LAT phosphorylation was lower in SIT–/– mice, the authors examined the activation status and phosphorylation of ZAP-70, the tyrosine kinase responsible for LAT phosphorylation. They found that SIT–/– mice had reduced phosphorylation at two critical ZAP-70 tyrosine residues, making SIT-deficient T cells refractory to TCR-mediated stimulation. Taken together, these data show that SIT negatively regulates peripheral T cell homeostasis through ZAP-70 signaling, thus changing the TCR activation threshold.
T Cell Tolerance in EAE
|
Summaries written by Kira R. Gantt, Ph.D.
Related articles in The JI:
| ||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
