IN THIS ISSUE

Follicular dendritic cells (FDC) are essential for germinal center architecture and function, but their role in regulating germinal center T cells is unclear. The small population (∼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-α, 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.

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-7Rα 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.

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.

Vaccination and infection have exposed the immune systems of most adults to influenza A H1N1 and H3N2 viruses. However, it is assumed that most individuals are immunologically naive to the H5N1 virus, also commonly referred to as avian influenza. Roti et al. (p. 1758 ) set out to test the hypothesis that the conservation of many proteins among influenza strains would lead to protection against the newly emerged H5N1 virus. Since the matrix protein and nucleoprotein of influenza A viruses are conserved and the H5N1 neuraminidase is of the same subtype as H1N1, it was not surprising that a strong CD4⁺T cell response was found in 15 out of 15 healthy subjects to the matrix protein, nucleoprotein, and neuraminidase of influenza A/Viet Nam/1203/2004 (H5N1) virus. What was surprising was that all of the healthy subjects tested had a CD4⁺T cell response to the less conserved H5N1 hemagglutinin protein. H5N1-reactive T cells secreting TNF-α, IFN-γ, 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.

When the tyrosine at amino acid 136 of linker for activation of T cells (LAT) is replaced with a phenylalanine (Lat^Y136F), mice develop a lymphoproliferative disorder characterized by Th2 cytokine-producing CD4⁺ T cells, severe inflammation, and autoantibody production. It has been thought that Lat^Y136F mice fail to eliminate self- reactive T cells during thymic negative selection and are left with a population of mature polyclonal CD4⁺ T cells that react with self-peptides bound to MHCII. However, Wang et al. (p. 1565 ) have shown that in fact, the Lat^Y136Fdisorder develops in the periphery in the absence of TCR:MHCII interactions. Using adoptive transfer of Lat^Y136F CD4⁺ T cells into mice lacking MHCII, the authors observed unabated lymphoproliferation and saw the hypergammaglobulinemia IgG1 and IgE that is characteristic of the Lat^Y136F disorder. The expansion of Lat^Y136F CD4⁺ T cells was dependent on the presence of IL-7. A population of nonfunctioning FoxP3⁺ regulatory T cells (Tregs) found in Lat^Y136F mutant mice had also been credited with causing the lymphoproliferative disorder. The authors demonstrated that Lat^Y136F CD4⁺ T cells were capable of escaping the control of wild-type FoxP3⁺ Tregs, indicating that the mutant defect is due to intrinsic hyperreactivity of the CD4⁺ T cells. Thus, the pathogenesis in these mice is Ag independent and, as such, cannot be considered truly autoimmune.

Paired Ig-like type 2 receptors (PILR), found on murine NK cells, macrophages, and dendritic cells, have an inhibitory isoform, PILRα, 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 PILRα 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.

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 CD44^highCD8⁺ 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.

Antigen-specific therapies are effective in treating experimental autoimmune encephalomyelitis (EAE) but have met with less success in treating human multiple sclerosis (MS). Chimeras created from the IgH chain CDR3 and proteolipid protein-1 (PLP1) or myelin oligodendrocyte glycoprotein (MOG) peptides have been shown to reverse CNS homogenate-induced EAE in SJL/J and C57BL/6 mice, respectively, through the induction of IL-10. To test the effectiveness of the chimera in a setting more relevant to human disease, Bell et al. (p. 1508 ) used MHC heterozygous mice created by breeding SJL/J and C57BL/6 animals. Treatment with Ig-PLP1 or Ig-MOG had no significant effect on CNS homogenate-induced EAE in (SJL/J × C57BL/6)F1 mice, indicating that the effectiveness of Ig-peptide chimeras will depend on the genetic background of the recipient and the corresponding dominant epitopes in the disease. Subsequent experiments in (SJL/J × C57BL/6)F1 mice with EAE induced by the administration of PLP1 or MOG peptides demonstrated that Ig-PLP1 or Ig-MOG treatment ameliorated PLP1/EAE but only Ig-MOG treatment could ameliorate MOG/EAE. However, Ig-PLP1 treatment produced PLP1-specific T cells producing IL-5 that blocked the production of anti-MOG Abs and exacerbated MOG/EAE. The authors demonstrated that in the context of genetic MHC polymorphism, in trans T cell tolerance can aggravate autoimmunity by suppressing a protective humoral response and complicates the consideration of Ag-specific therapy.

Summaries written by Kira R. Gantt, Ph.D.