Getting to Know Qa-1b
The nonclassical MHC molecule HLA-E presents leader peptides der-ived from MHC class I molecules. HLA-E plays an impor-tant role in human NK cell activation by interacting with CD94-NKG2 receptors and can also stimulate adaptive immunity by presenting Ags to CD8+ T cells. In mice, Qa-1b serves as the HLA-E ortholog, yet little is known about the molecular basis of its function or its evolutionary relation-ship to HLA-E. In this issue, Zeng et al. (p. 302) present the crystal structure of Qa-1b in complex with its most com-monly associated peptide, Qdm, and address its structure and function relative to those of HLA-E. The Qa-1b–peptide complex bound to mouse CD94-NKG2A with low affinity and exhibited no binding to human CD94-NKG2A, nor did HLA-E peptide complexes bind to mouse CD94-NKG2A. Analysis of the Qa-1b peptide crystal structure revealed many similarities to that of HLA-E, with the bound Qdm peptide assuming an extended conformation. The peptide-binding groove had five binding pockets that strongly constrained the peptide repertoire able to bind to Qa-1b. Des-pite a very similar overall structure, HLA-E and Qa-1b dem-onstrated differences in their peptide-binding grooves and CD94-NKG2A contact residues. This study provides useful structural insight into the roles of Qa-1b in innate and ad-aptive immunity.
Nuclear Membrane Necessities
The inner nuclear membrane protein lamin B receptor (LBR) has been suggested to be involved in nuclear architecture maintenance and gene silencing through its interactions with the nuclear lamina and heterochromatin. In mice, the in vivo activity of this protein has been difficult to assess because LBR deficiency is fatal. In this issue, Verhagen et al. (p. 122) characterized mice, designated Lym3, bearing a point mutation in the Lbr gene that dramatically reduces LBR expression but allows normal embryonic development. These mice demonstrated severe, progressive T cell lymphopenia and reduced neutrophil lobularity despite normal thymic and bone marrow development. Lymphopenia was asso-ciated with impaired homeostatic proliferation and decreased survival of T cells. These T cell impairments were observed despite a lack of significant differences between TCR signaling in wild-type and Lym3 T cells. Although LBR inter-acted with heterochromatin, the Lym3 mutation did not glob-ally affect gene expression in CD8+ T cells or neutrophils. However, in both Lym3 T cells and neutrophils, a common subset of genes tended to be upregulated, suggesting a role for LBR in the suppression of these genes. This study reveals LBR as an important player in multiple aspects of proper immune function.
IL-17 Loses Clout
Th1 cells have long been thought to be responsible for the pathogenesis of organ-specific autoimmune diseases. However, this idea was called into question by the discovery of Th17 cells and the recognition of their importance in the development of multiple sclerosis and rheumatoid arthritis. In autoimmune diabetes, there is indirect evidence for a pathogenic role for Th17 cells, but a conclusive demonstration of involvement of these cells is still lacking. To directly assess the role of IL-17 in diabetes, Joseph et al. (p. 216) generated a line of NOD mice in which expression of the Il17a gene was silenced by short hairpin RNA (IL-17 KD mice). T cells in these mice expressed significantly reduced levels of IL-17 but were not impaired in the expression of IL-17F, IL-21, or RORγt, suggesting that Th17 differentiation was intact. Surprisingly, there were no differences between IL-17 KD and wild-type NOD mice in the development of either spontaneous or cyclophosphamide-induced diabetes. The effectiveness of IL-17 knockdown was validated in a model of experimental autoimmune encephalomyelitis, in which the IL-17 KD mice were significantly protected from the disease that developed in wild-type NOD mice. These data indicate that the signature cytokine of Th17 cells is not necessary for the development of autoimmune diabetes in NOD mice and that Th17 function cannot be assumed to be important in all organ-specific autoimmunity.
Sphingosine 1-phosphate (S1P) is important in lymphocyte trafficking and vascular biology and, to-gether with the type 1 S1P receptor (S1P1), appears to pro-mote the pathogenesis of auto-immune diseases such as rheumatoid arthritis. Counterintu-itive data have indicated that S1P1 agonists, rather than an-tagonists, can serve as clinically useful immunosuppressants. To address this discrepancy and clarify the role of S1P–S1P1 in immunity, Fujii et al. (p. 206) developed a selective S1P1 antagonist, TASP0277308, and found that its activities in vivo recapitulated the phenotype of lymphocytes deficient in S1P1. Administration of this antagonist induced lymphopenia and inhibited thymic egress. Similarly to S1P1 agonists like FTY720, the antagonist caused splenic B cells to leave the marginal zone and enter the follicles. Unlike S1P1 agonists, TASP0277308 induced CD69 upregulation on thymocytes, B cells, and both CD4+ and CD8+ T cells. TASP0277308 suppressed the development of collagen-induced arthritis and also demonstrated efficacy in the treatment of ongoing arthritis. The ability of the antagonist to stimulate CD69 expression suggests that it could have greater therapeutic efficacy than the S1P1 agonists, which downregulate CD69 and thereby reduce expression of the immunomodulatory cytokine TGF-β. These data logically agree with in vitro data describing the function of the S1P–S1P1 interaction and suggest that S1P1 agonists such as FTY720 may in fact act as “functional antagonists” by inducing the internalization of S1P1 following stimulation.
Bone Marrow-Mediated IgM
Long-lived plasma cells in the bone marrow maintain memory to T cell-dependent Ags. Serum titers of IgM-dominated anti-polysaccharide Abs are also maintained long term, but it is not clear whether these Abs are indicative of persistent Ag presence or the establishment of long-lived plasma cells. To address this question, Foote et al. (p. 57) analyzed the B cell response to α 1→3-dextran (DEX), either alone or as a bacterial component. DEX-specific Ab production was sustained long term by IgM Ab-secreting cells (ASCs) in the bone marrow and spleen. In the spleen, the DEX Ag was found to persist, and the ASC population consisted of short-lived plasmablasts undergoing rapid turnover. In contrast, DEX did not persist long-term in the bone marrow, and the bone marrow ASC population was found to be quiescent and long-lived. The splenic ASCs, but not the bone marrow ASCs, were sensitive to cyclophosphamide-mediated cell death. Serum anti-DEX Abs remained stable despite cyclophosphamide treatment or anti-CD20–mediated B cell depletion, suggesting that the bone marrow ASC population was responsible for the maintenance of these anti-polysaccharide Abs. This study indicates that T-independent polysaccharide Ags can induce the development of a long-lived plasma cell-like population in the bone marrow.
PTPN22’s Place in Autoimmunity
Autoimmune disease arises from complex interactions between environmental factors and genetic variation. PTPN22 encodes the lymphoid tyrosine phospha-tase Lyp. The Lyp 1858T missense mutation results in the Lyp620W isoform, which leads to impaired BCR signaling and is associated with susceptibility to multiple autoimmune diseases. Habib et al. (p. 487) assessed the role of Lyp620W in B cell tolerance by studying the B cells of healthy individ-uals heterozygous for PTPN22 1858T. Compared with con-trol individuals, these heterozygous individuals had a greater frequency of peripheral transitional B cells and anergic naive IgD+IgM− B cells, suggesting an enhanced representation of autoreactive B cells. Transitional and naive B cells in these individuals demonstrated decreased phosphorylation of PLCγ2 and an altered BCR signaling threshold relative to controls. These B cells also underwent less BCR-mediated apoptosis, suggesting that the Lyp620W variant interfered with efficient negative selection. Interestingly, patients with type I diabetes had alterations in their B cell compartments and impairments in BCR signaling similar to those in healthy heterozygous Lyp620W-expressing individuals; however, these effects did not require the PTPN22 1858T variant. These data suggest a mechanism by which Lyp620W may contribute to the breakdown of B cell tolerance and indicate that additional factors interact with Lyp to disturb tolerance in type I diabetes.
Summaries written by Jennifer Hartt Meyers, Ph.D.