Interferon-inducible gene 202b controls CD8+ T cell-mediated suppression in anti-DNA Ig peptide-treated (NZB × NZW) F1 lupus mice

Administration of an artificial peptide (pConsensus) based on anti-DNA IgG sequences that contain major histocompatibility complex class I and class II T-cell determinants, induces immune tolerance in NZB/NZW F1 female (BWF1) mice. To understand the molecular basis of CD8+ Ti-mediated suppression, we previously performed microarray analysis to identify genes that were differentially expressed following tolerance induction with pCons. CD8+ T cells from mice tolerized with pCons showed more than two-fold increase in Ifi202b mRNA, an interferon inducible gene, versus cells from untolerized mice. Ifi202b expression increased through weeks 1–4 after tolerization and then decreased, reapproaching baseline levels at 6 weeks. In vitro polyclonal activation of tolerized CD8+ T cells significantly increased Ifi202b mRNA expression. Importantly, silencing of Ifi202b abrogated the suppressive capacity of CD8+ Ti cells. This was associated with decreased expression of Foxp3, and decreased gene and protein expression of transforming growth factor (TGF)β and interleukin-2 (IL-2), but not of interferon (IFN)-γ, IL-10, or IL-17. Silencing of another IFN-induced gene upregulated in tolerized CD8+ T cells, IFNAR1, had no effect on the ability of CD8+ T cells to suppress autoantibody production. Our findings indicate a potential role for Ifi202b in the suppressive capacity of peptide-induced regulatory CD8+ Ti cells through effects on the expression of Foxp3 and the synthesis of TGFβ

Multiple loci are linked with anti-red blood cell antibody production in NZB mice – comparison with other phenotypes implies complex modes of action

The New Zealand Black (NZB) mouse strain is a model of autoimmune haemolytic anaemia (AHA) and systemic lupus erythematosus (SLE), characterized by the production of anti-red blood cell (RBC) antibodies and anti-nuclear antibodies (ANA), respectively. A linkage analysis was carried out in an (NZB × BALB/c) F(2) cross in order to identify loci involved in the production of both anti-RBC IgM and IgG antibodies. These regions of linkage were compared with linkage data to ANA from the same cohort and other linkage analyses involving New Zealand mice. Four previously described NZB loci linked to anti-RBC antibodies were confirmed, and eight novel loci linked to this trait were also mapped: five of which were of NZB origin, and three derived from the non-autoimmune BALB/c background. A comparison between loci linked with anti-RBC antibodies and ANA demonstrated many that co-localize, suggesting the presence of genes that result in the general breaking of tolerance to self-antigen. Furthermore, the observation that some loci were associated only with the anti-RBC response suggests an antigen specific mechanism in addition to a general breaking of tolerance. A locus linked with anti-RBC antibodies and ANA on distal chromosome 7 in this cohort is orthologous to one on the q arm of human chromosome 11, a region linked to AHA and ANA in human SLE

Identification of systemically expanded activated T cell clones in MRL/lpr and NZB/W F1 lupus model mice

CD4(+) T lymphocytes play an important role in the pathogenesis of systemic lupus erythematosus (SLE). To characterize the clonal expansion of CD4(+) T cells in murine lupus models, we analysed the T cell clonality in various organs of young and nephritic MRL/lpr and NZB/W F1 mice using reverse transcription–polymerase chain reaction (RT-PCR) and subsequent single-strand conformation polymorphism (SSCP) analysis. We demonstrated that some identical T cell clonotypes expanded and accumulated in different organs (the bilateral kidneys, brain, lung and intestine) in nephritic diseased mice, and that a number of these identical clonotypes were CD4(+) T cells. In contrast, young mice exhibited little accumulation of common clones in different organs. The T cell receptor (TCR) Vβ usage of these identical clonotypes was limited to Vβ2, 6, 8·1, 10, 16 and 18 in MRL/lpr mice and to Vβ6 and 7 in NZB/W F1 mice. Furthermore, some conserved amino acid motifs such as I, D or E and G were observed in CDR3 loops of TCRβ chains from these identical CD4(+) clonotypes. The existence of systemically expanding CD4(+) T cell clones in the central nervous system (CNS) suggests the involvement of the systemic autoimmunity in CNS lesions of lupus. FACS-sorted CD4(+)CD69(+) cells from the kidney displayed expanded clonotypes identical to those obtained from the whole kidney and other organs from the same individual. These findings suggest that activated and clonally expanded CD4(+) T cells accumulate in different tissues of nephritic lupus mice, and these clonotypes might recognize restricted T cell epitopes on autoantigens involved in specific immune responses of SLE, thus playing a pathogenic role in these lupus mice

Expression patterns of signaling lymphocytic activation molecule family members in peripheral blood mononuclear cell subsets in patients with systemic lupus erythematosus

Genome-wide linkage analysis studies (GWAS) studies in systemic lupus erythematosus (SLE) identified the 1q23 region on human chromosome 1, containing the Signaling Lymphocytic Activation Molecule Family (SLAMF) cluster of genes, as a lupus susceptibility locus. The SLAMF molecules (SLAMF1-7) are immunoregulatory receptors expressed predominantly on hematopoietic cells. Activation of cells of the adaptive immune system is aberrant in SLE and dysregulated expression of certain SLAMF molecules has been reported. We examined the expression of SLAMF1-7 on peripheral blood T cells, B cells, monocytes, and their respective differentiated subsets, in patients with SLE and healthy controls in a systematic manner. SLAMF1 levels were increased on both T cell and B cells and their differentiated subpopulations in patients with SLE. SLAMF2 was increased on SLE CD4+ and CD8+ T cells. The frequency of SLAMF4+ and SLAMF7+ central memory and effector memory CD8+ T cells was reduced in SLE patients. Naïve CD4+ and CD8+ SLE T cells showed a slight increase in SLAMF3 levels. No differences were seen in the expression of SLAMF5 and SLAMF6 among SLE patients and healthy controls. Overall, the expression of various SLAMF receptors is dysregulated in SLE and may contribute to the immunopathogenesis of the disease