In Brief

Autoimmunity

Human lupus T cells resist inactivation and escape death by upregulating COX-2. Zu, L. et al. Nature Med. 10, 411–415 (2004)

This study used microarray analysis to look at why CD4⁺ T helper (T_H) cells from patients with systemic lupus erythematosus (SLE) are resistant to anergy and activation-induced cell death (AICD). They show that the PTGS2 gene, which encodes COX2, is upregulated in T_H cells from patients with SLE. COX2 expression protects T_H cells from death by upregulating expression of the anti-apoptotic protein c-FLIP and decreasing signalling through the FAS (CD95) apoptotic pathway. COX2 overexpression did not result in prostaglandin E₂ production by the T_H cells, which indicates that COX2 has a role in transcriptional regulation that does not depend on its enzymatic activity. This could lead to the development of selective inhibitors of the COX2 anti-apoptotic pathway.

Lymphopoiesis

Development of a human adaptive immune system in cord blood cell-transplanted mice. Traggiai, E. et al. Science 304, 104–107 (2004)

To overcome the limitations of studying development of the human immune system in vitro, researchers have long sought to develop an in vivo model involving transplantation of human cells into immunodeficient mice. A new system reported in this paper has for the first time led to the formation of a functional adaptive immune response. The authors transplanted CD34⁺ human cord-blood precursors into the liver of newborn Rag2^−/−γc^−/− mice and analysed them up to 6 months of age. They showed that the development of human T cells, B cells and dendritic cells occurred normally in the xenotransplanted mice and resulted in the formation of organized lymphoid structures. Furthermore, the mice mounted a good immune response to vaccination with tetanus toxoid or infection with Epstein–Barr virus.

Autoimmunity

Coxsackieviral-mediated diabetes: induction requires antigen-presenting cells and is accompanied by phagocytosis of β cells. Horwitz, M. S. et al. Clin. Immunol. 110, 134–144 (2004)

This study indicates a crucial role for antigen-presenting cells in initiating the destruction of pancreatic β-cells induced by viral infection. Epidemiological studies have shown a link between infection with coxsackie B virus (CBV) and type 1 diabetes. To investigate the pathogenic process, Sarvetnick and colleagues used a diabetes model involving infection of islet-specific T-cell receptor (TCR)-transgenic mice with CBV strain 4 (CB4). They show that CB4 infects insulin-producing β-cells without causing necrosis. Instead, the stressed islet cells are phagocytosed by resident macrophages, which present islet epitopes to autoreactive T cells. These macrophages could induce diabetes after adoptive transfer to uninfected TCR-transgenic mice. Therefore, viral infection could be the last initiating step in multi-step diabetes development, requiring the pre-existence of autoreactive T cells.

Innate Immunity

Effects of mosquito genes on Plasmodium development. Osta, M. A., Christophides, G. K. & Kafatos, F. C. Science 303, 2030–2032 (2004)

Previous analysis of the Anopheles gambiae genome, a mosquito vector for Plasmodium, identified 242 genes as potential mediators of innate immunity. In this study, the function of three of these genes was investigated by gene silencing. Functional deletion of two C-type lectins (CTLs), CTL4 and CTLMA2, resulted in the death of most Plasmodium ookinetes, indicating that these two CTLs protect parasites during development. By contrast, lack of leucine-rich-repeat immune gene (LRIM) function resulted in increased numbers of Plasmodium oocysts, providing evidence that LRIM antagonizes Plasmodium development. The identification of mosquito proteins that have positive and negative effects on Plasmodium provides new avenues of research in the quest to control malaria through the mosquito vector.

Lymphocyte Migration

Activated primary and memory CD8 T cells migrate to nonlymphoid tissues regardless of site of activation or tissue of origin. Masopust, D. et al. J. Immunol. 172, 4875–4882 (2004)

This study examines whether the site of antigen encounter determines the extralymphoid migratory properties of activated CD8⁺ T cells. Antigen-specific CD8⁺ T cells activated by localized intestinal viral infection were found not only in the intestine but also in other non-lymphoid tissues. This widespread distribution was observed for both the primary effector cells and virus-specific memory cells. Furthermore, memory CD8⁺ T cells from non-lymphoid tissues, other than the intestinal mucosa, retained the ability to disseminate into multiple extralymphoid sites, albeit with some preference for their site of isolation. These findings have implications for immunotherapies that induce antigen-specific immunity or regulate disease by controlling T-cell migration.

Antigen Presentation

MHC class I molecules expressed with monoglucosylated N-linked glycans bind calreticulin independently of their assembly status. Wearsch, P. A. et al. J. Biol. Chem. 31 March 2004 (doi:10.1074/jbc.M401721200)

This study used a novel glycosylation mutant strain of Saccharomyces cerevisiae, which could produce MHC class I molecules bearing the transient oligosaccharide intermediates recognized by calreticulin — monoglucosylated N-linked glycans — to investigate the precise role of this chaperone in generating peptide–MHC class I complexes. Calreticulin binding to these MHC class I molecules was dependent on the N-linked glycan, and specifically on the glucose residue. Calreticulin was found to bind correctly glycosylated MHC class I molecules irrespective of their conformation — free MHC class I heavy chains, empty MHC class I-β₂-microglobulin heterodimers and peptide-loaded MHC class I complexes — providing support for the hypothesis that by binding monoglucosylated N-linked glycans calreticulin cannot determine the conformation of the protein.