It is thought that transmissible spongiform encephalopathies, otherwise known as “prion diseases,” can be transmitted through oral exposure to misfolded prion proteins (PrPSc). These proteins then accumulate in follicular dendritic cells found in GALT B cell follicles before journeying to the CNS, a process termed neuroinvasion. Raymond et al. (p. 7758 ) found that this journey is mediated by CD11c+ dentritic cells (DCs). By using mice transgenic for CD11c-diptheria toxin receptor (CD11c-DTR), the authors were able to use diphtheria toxin (DT) to transiently remove CD11c+ DCs at the time of PrPSc administration. The administration of two different scrapie agents 24 h after DT treatment resulted in no staining of PrPSc in the Peyer’s patches 70 or 105 days after inoculation. However, control mice showed strong accumulations of PrpSc in the Peyer’s patches at these same time periods. There was no transfer of misfolded prions to the mesenteric lymph nodes and spleens of DT-treated CD11c-DTR mice. These mice also had a lower incidence of disease (∼40–60%) compared with untreated mice. When the PrPSc agent was administered directly into the CNS all mice had the same incidence of disease, confirming the role of GALT CD11c expression in disease transmission. CD11c+ DCs clearly play an important part in disease susceptibility and transmission of TSE agents from the gut lumen to the GALT and eventually to the CNS.

Secretory IgA (SIgA) has long been known to selectively bind to M cells in Peyer’s patches (PPs). This allows the immune system to sample the gut and direct Ags to dendritic cells (DCs) and lymphoid tissues. Kadaoui et al. (p. 7751 ) show that only myeloid DCs expressing CD11b and CD11c are capable of binding and internalizing SIgA, while CD11c+/CD19+ DCs can bind but not internalize SIgA. Competition experiments showed that this binding and internalization was specific to IgA and could not be mediated by IgG or IgM. This process was tissue restricted, as DCs from PPs and mesenteric lymph nodes bound SIgA but DCs from bronchial or inguinal lymph nodes and spleen could not. Because DCs from the PPs lost their ability to internalize SIgA complexed with bacteria once isolated in vitro, the authors tested the uptake of fluorescently labeled SIgA:Shigella flexneri complexes in the mouse using a ligated intestinal loop model. Not only were DCs capable of internalizing the Ab:bacteria complex, but fluorescently tagged S. flexneri were found 4 h later in the T cell-rich regions of draining mesenteric lymph nodes. No bacterial translocation to the intestinal epithelium was found without the associated SIgA, indicating a selective Ag delivery process. Whereas the receptor that mediates this transfer is still unknown, the delivery of specific SIgA:Ag complexes from the gut to the mesenteric lymph nodes clarifies how the pathway to mucosal homeostasis is achieved.

Mature and memory B cells produce a membrane-bound form of the Ig heavy chain (IgH), whereas plasma cells mostly produce a secretory form of the protein. In addition, IgH mRNA levels are 20- to 50-fold higher in plasma cells than in mature or memory B cells while transcription rates stay the same. Shell et al. (p. 7663 ) have found that the increased mRNA production and change in transcript are due to increased phosphorylation of the RNA polymerase II (RNAP-II) carboxyl-terminal domain (CTD) and the subsequent recruitment of RNA elongation and polyadenylation factors such as ELL2 and PC4 to the 5′ end of the IgH gene. The use of a cell line with a plasma cell phenotype demonstrated that increased serine phosphorylation of the RNAP-II CTD was found at the 5′ end of the IgH gene when compared with the same region in a memory B cell line. This change in polymerase phosphorylation caused a differential loading of several transcription factors on the IgH gene in the plasma cell and polymerase selection of the secretory poly(A) site. CPSF-160, CstF-50, Cst-64, ELL4, and PC4, factors involved in elongation and polyadenylation, were increased on the 5′ end of the IgH gene as a result of the phosphorylation. Blocking of the serine phosphorylation with an inhibitor reversed this recruitment of RNA transcription factors. These changes in RNA processing and polyadenylation site selection clarify how plasma cells make the switch to a secretory form of IgH.

Without TNF, granulomas formed during Mycobacterium avium infection eventually lose their architecture and can no longer restrict disease. This leads to extensive apoptosis and necrosis, and the animals die shortly after granuloma disintegration. Using TNF-deficient mice infected with M. avium, Flórido and Appelberg (p. 7702 ) examined the effect of cytokine loss in disease after granuloma disintegration. M. avium-infected TNF−/− mice survived only half as long as their wild-type counterparts before succumbing to disease. Proliferation of CD4+ and CD8+ T cells was greater in infected TNF−/− mice, and much higher levels of IFN-γ were found both in sera and in cell cultures obtained from these mice. Liver granulomas undergoing disintegration could be seen in moribund mice, which had massive lung infiltrates that consisted of mononuclear cells, foci of lymphocyte accumulation, areas of necrosis, and apoptotic cells. The authors also overexpressed Bcl-2 in TNF−/− mice infected with M. avium and found that this antiapoptotic protein slightly improved survival times. While Fas ligand expression on T cells from the lung stayed the same, the level of TRAIL increased on T cells and monocytes in the lungs of TNF−/− mice compared with wild-type mice. This led to the hypothesis that increased apoptosis contributes to granuloma disintegration and the eventual death of the mice. TNF is clearly necessary to control mycobacterial disease because without it granuloma architecture disintegrates and causes a volatile release of IFN-γ.

Receptor activator of NF-κB ligand (RANKL) is essential for osteoclast function, and ligation of its receptor, RANK, leads to bone resorption. Osteoprotegerin (OPG), a soluble decoy receptor and endogenous inhibitor of RANKL, is under investigation as a potential therapy against bone loss. Because total ablation of RANKL leads to severe immune dysfunction, Stolina et al. (p. 7497 ) created rats over-expressing a soluble form of OPG (OPG-Tg) and examined whether prenatal expression of OPG could suppress RANKL, increase bone mass, and maintain immune development. OPG-Tg rats produced ∼100 fold more OPG at gestational day 11 than wild-type rats; yet, unlike RANKL knockout animals, OPG-Tg rats had increased bone mass and normal lymph node and thymic development. Adult OPG-Tg rats also had normal lymphoid organs by histological examination. The continuous RANKL inhibition increased bone density in adult animals as indicated by physical examination and a reduction in the bone resorption marker TRAP-5B. OPG-Tg animals also had normal numbers of lymphocytes, granulocytes, and monocytes in the peripheral blood, with normal delayed-type hypersensitivity responses to oxazolone. OPG overexpression did not affect humoral responses to the T cell-dependent Ag keyhole limpet hemocyanin. Thus, future OPG-based therapies may increase bone mass without demonstrable immune side effects.

Interleukin-7 is responsible for the survival and development of both CD4+ and CD8+ T cells, and the receptor IL-7Rα (CD127) can determine effector T cell fate. Lim and Kim (p. 7448 ) have shown that the loss of CD127 expression in the human tonsil created terminally differentiated B cell-helping effector T cells. CD127 T cells expressed high levels of CXCR5 and low levels of CCR7, were localized in the tonsil germinal centers, and produced the B cell zone chemokine CXCL13 in response to Ag stimulation. Chemokine production by CD127 T cells was greatly enhanced by coculture with syngeneic B cells. Not surprisingly, because IL-7 promotes the survival of T cells, the lack of CD127 increased apoptosis. Memory/activated CD4+CD127 T cells had shorter telomeres, less Bcl-2 expression, and higher spontaneous death rates compared with CD4+CD127+ T cells. Although CD4+CD127 T cells were unresponsive to IL-7 and proliferated poorly, they were highly efficient at helping B cells produce the full range of Igs through a CD40L- and ICOS-mediated mechanism. This distinguishes CD127 T cells as the predominant source of B cell help leading to effective Ig production in tonsil germinal centers.

T cell progenitors are positively selected based on TCR:MHC interactions, with MHC II selecting CD4+ cells and MHC I selecting CD8+ cells. After positive selection, T cell migration to the thymic medulla is mediated by CCR7. Yin et al. (p. 7358 ) found that CD4+CD8+ thymocytes undergoing positive selection through MHC I had higher expression of CCR7 when comparing thymocytes from mice expressing MHC I vs MHC II transgenes. This CCR7 expression correlated with higher migratory capability; more cells from MHC I-selected CD4+CD8+ thymocytes (14.9%) migrated to the CCR7 ligand CCL21 as compared with MHC II-selected thymocytes (0.74%). Mice lacking Th-POK, a zinc finger transcription factor responsible for CD4+ T cell differentiation, and expressing the MHC II TCR transgene AND were used to look at the role of CCR7 in lineage commitment. AND+/− Th-POK−/− mice had an increase in both double positive thymocytes expressing CCR7 and mature CD4CD8+ thymocytes and had a decrease in mature CD4+CD8 thymocytes, correlating CD8 lineage commitment to CCR7 expression. Accordingly, thymic overexpression of CCR7 led to increased numbers of mature CD8+ thymocytes. Thus, early and robust expression of CCR7 can influence the phenotypic fate of thymocytes, suggesting that the importance of the TCR:MHC signal may partly lie in how long the TCR:MHC interaction lasts.

Autoantigens in systemic lupus erythematosus are thought to develop from the release of apoptotic material. Both humans and mice with excessive apoptotic debris, such as fragmented chromatin and RNA:protein complexes, have increased autoantibody production and develop lupus or similar syndromes. Frisoni et al. (p. 7959 ) used a recently created transgenic mouse lacking caspase-activated DNase (CAD) endonuclease to prove that the release of apoptotic debris is responsible for autoantibody production. Pristane-injected CAD−/− and CAD+/+ mice developed a lupus-like syndrome, but mice lacking CAD showed no evidence of DNA fragmentation. CAD−/− mice did not generate anti-chromatin Abs, whereas their Ig response to the membrane phospholipid cardiolipin, another marker of apoptosis, was still present. No significant differences in numbers of T cells, B cells, or macrophages were found between CAD+/+ and CAD−/− mice, and T cell-dependent humoral responses to OVA were unimpaired. Thus despite functional Ig responses in CAD−/− mice, antinuclear Abs were not produced in the absence of apoptotic DNA fragmentation However, the lack of nuclear autoantibody targets did not slow kidney disease in the CAD−/− mice, indicating that disease progression may be unaffected by whether the initial autoantigen target is nuclear or cytoplasmic.

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