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Prions and Complement
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wild type or wild typeCD21/35–/–) demonstrated a requirement for CD21/35 expression on stromally derived cells, presumably follicular dendritic cells (FDCs), for prion accumulation and retention. Interestingly, bone marrow chimeras lacking CD21/35 on B cells also demonstrated a delay in disease progression, indicating that FDCs are not the only CD21/35+ cells required for efficient prion disease pathogenesis. However, the data implicated CD21/35 on FDCs as important in targeting prions to FDCs and in subsequent disease development. IFN, IL-17, and Arthritis
Interferon-
can act to both mitigate and exacerbate autoimmune inflammation. Irmler et al. (p. 6228
) analyzed the role of IFN- in Ag-induced arthritis (AIA), a model of rheumatoid arthritis, and found that mice lacking this cytokine demonstrated significantly increased inflammation vs controls in the early acute phase of AIA. This disease exacerbation was accompanied by increased neutrophil infiltration into the affected joint and an attenuated humoral response as compared with wild-type mice. An augmented CD4+ T cell response was also observed in IFN--deficient mice and was accompanied by elevated levels of numerous cytokines, most notably IL-17. IL-17 has been shown to serve as an important inflammatory mediator in multiple autoimmune diseases, including arthritis, and its production therefore supported the hypothesis that IFN- suppresses inflammation in AIA. In vivo treatment with either IFN- or neutralizing anti-IL-17 reversed the inflammatory effects of IFN- deficiency, and IFN- could inhibit the development of IL-17-producing CD4+ T cells in vitro. These data indicate that IFN- plays a protective role in the early stage of AIA, inhibiting the cellular but not the humoral inflammatory response.
Longevity Isn’t Everything
The duration of a dendritic cell (DC):T cell interaction profoundly impacts the ensuing T cell response, and it has been suggested that CD4+ T cell help to CD8+ T cells may involve prolonging DC survival. To determine whether CD4+ T cells indeed promote DC survival and thereby enhance CD8+ T cell responses, Matthews et al. (p. 5738 ) compared CD8+ T cell responses elicited by DCs either expressing or lacking MHC II. Mice injected with MHC II–/– DCs demonstrated impaired DC survival in their lymph nodes compared with mice injected with wild-type DCs. In addition, these knockout DCs induced a truncated, less potent CD8+ T cell response compared with that induced by wild-type DCs, even if the knockout DCs were activated in vitro before transfer. The authors found that in vitro pre-treatment of MHC II–/– DCs with either a high dose of LPS or a low dose of LPS combined with CD40L could enhance DC survival in vivo. Interestingly, these treatments did not restore the subsequent CTL response, indicating that increased DC survival cannot replace the requirement for CD4+ T cell help to CD8+ T cells.
Class I Architecture
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Notch Ligands in EAE
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could augment, Jagged1 expression. Understanding the dichotomous roles played by Notch ligands in this organ-specific autoimmune disease advances our knowledge of both autoimmune progression and Notch function. KIR Hierarchy
Human NK cells express a variety of inhibitory receptors that recognize MHC class I, and it has been demonstrated that these receptors are required not only for maintenance of self-tolerance but also for NK cell functional competence. Yu et al. (p. 5977
) undertook a systemic single-cell analysis of human NK cell functionality and determined several principles of inhibitory NK receptor function. NK cells expressing killer Ig-like receptors (KIR) specific for self-MHC I had increased effector capacity vs NK cells expressing receptors with broader specificity, which were themselves more responsive than NK cells expressing KIR specific for non-self MHC. An additive effect in responsiveness, as measured by IFN- production and cytotoxicity, was observed with increasing numbers of different self-specific KIR expressed in a single cell. However, the number of KIR expressed per cell was inversely correlated with the number of NK cells present, supporting a serial acquisition model of inhibitory receptor expression. Surprisingly, NK cells expressing more than one KIR required interaction with only a single MHC ligand to prevent their activation. These observations of a diverse functional NK cell repertoire with preferential expression of self-specific KIR have broad applications for understanding of NK cell tolerance and activation.
Modeling Burkitt Lymphoma
Human Burkitt lymphoma (BL) involves translocation of c-myc into one of the Ig loci, most often the IgH locus. Truffinet et al. (p. 6033 ) asked whether the 3' IgH locus control region (3' LCR) alone could dysregulate c-myc and cause lymphomagenesis. The authors developed a transgenic mouse carrying an isolated cassette consisting of a c-myc transgene under the control of the 3' LCR, which allowed for c-myc dysregulation in a B cell-specific manner and mimicked a c-myc translocation into the IgH locus. B cell development occurred normally in these mice, but their B cells proliferated and underwent spontaneous apoptosis at a significantly higher rate than B cells in wild-type mice. Most interestingly, these mice spontaneously developed B cell lymphomas at a much faster rate than other mouse models exhibiting the features of BL. The majority (75%) of these lymphomas were lymphoblastic B cell lymphomas with the defining features of BL, whereas the other 25% were characterized as diffuse anaplastic lymphomas. This transgenic mouse indicates the major role that the 3' LCR may play in BL development, and may also serve as a useful model system for future study of the development and treatment of BL.
Shared Epitope Mechanism
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Summaries written by Jennifer Hartt Meyers, Ph.D.
Related articles in The JI:
-Deficient Mice As a Result of Unrestricted IL-17 Response
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