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Transcriptional Modulation of TCR, Notch and Wnt Signaling Pathways in SEB-Anergized CD4+ T Cells

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Transcriptional Modulation of TCR, Notch and Wnt Signaling Pathways in SEB-Anergized CD4+ T Cells Genes and Immunity (2005) 6, 596–608 & 2005 Nature Publishing Group All rights reserved 1466-4879/05 $30.00 www.nature.com/gene FULL PAPER Transcriptional modulation of TCR, Notch and Wnt signaling pathways in SEB-anergized CD4 þ T cells S Kurella1, JC Yaciuk1,2, I Dozmorov1, MB Frank1, M Centola1 and AD Farris1,2 1Arthritis and Immunology Program, Oklahoma Medical Research Foundation, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; 2Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA Gene expression changes in CD4 þ Vb8 þ T cells anergized by in vivo exposure to staphylococcal enterotoxin B (SEB) bacterial superantigen compared to CD4 þ Vb8 þ nonanergic T cells were assessed using DNA microarrays containing 5184 murine complementary DNAs. Anergy in splenic T cells of SEB-immunized BALB/c mice was verified by dramatically reduced proliferative capacity and an 8 Â overexpression of GRAIL mRNA in CD4 þ Vb8 þ T cells taken from mice 7 days after injection. At an Associative t-test threshold of Po0.0005, 96 genes were overexpressed or detected only in anergic T cells, while 256 genes were suppressed or not detected in anergic T cells. Six of eight differential expressions tested using real-time quantitative PCR were validated. Message for B-Raf was detected only in non-anergic cells, while expression of the TCR signaling modulator Slap (Src-like adapter protein) and the TCR z-chain specific phosphatase Ptpn3 was enhanced. Modulation of multiple genes suggests downregulation of Wnt/b-catenin signaling and enhanced Notch signaling in the anergic cells. Consistent with previous reports in a non-superantigen in vivo anergy model, mRNA for CD18 and the transcription factor Satb1 (special AT-rich-binding protein 1) was increased in SEB-anergized T cells. This is the first report of global transcriptional changes in CD4 þ T cells made anergic by superantigen exposure. Genes and Immunity (2005) 6, 596–608. doi:10.1038/sj.gene.6364245; published online 21 July 2005 Keywords: T cell; anergy; superantigen; rodent; microarray Introduction of CD4 þ Vb8 þ T cells precedes death and anergy in sequential stages of the immune response,5 such that, Naturally acquired T-cell tolerance to self-antigens is seven or more days postexposure, remaining nondeleted accounted for by several known mechanisms (reviewed CD4 þ Vb8 þ T cells are anergic. Studies using this in Nakken et al1) including clonal deletion, anergy and established model have shown defective TCR z-chain immunoregulatory cell control. Anergy is a tolerance phosphorylation,9 defective calcium signaling10,11 and mechanism in which lymphocytes are intrinsically intact Ras/MAP kinase signaling at very early time functionally inactivated following antigen encounters points,11 characteristics consistent with an adaptive, or in that produce suboptimal or altered signaling.2–6 Such vivo type of anergy. Reports of the reversibility of SEB- cells remain alive for extended periods of time in a induced anergy by IL-24,12,13 and the degree to which hyporesponsive state and are characterized by defective nongrowth-dependent effector functions are impaired or IL-2 production and cell cycle arrest.7,8 Although these intact in this model14–16 are conflicting. Interestingly, SEB- qualities appear to be universal traits of anergic T cells, induced T-cell anergy appears to target primarily cells several other characteristics have been used to subdivide with a memory phenotype,17,18 a property usually anergic states into two broad and likely nonmutually associated with clonally anergic cells. These studies exclusive categories that differ in several aspects, suggest that the SEB model invokes selective character- including major modes of biochemical signaling block- istics of both clonal and adaptive anergy, presenting a ade, reversibility by IL-2, shutdown of nongrowth- unique opportunity to appreciate additional factors dependent effector functions and susceptibility of involved in anergy induction and maintenance. memory vs naı¨ve cells to anergy induction.7 Initiation of the anergic program requires new protein In BALB/c mice systemically exposed to staphylococ- synthesis that is likely to also be necessary for main- cal enterotoxin B (SEB) superantigen, clonal expansion tenance of the anergic state.19,20 In addition, cell fusion studies have shown that the anergic phenotype is dominant.21 Several classes of putative ‘anergy’ factors Correspondence: Dr AD Farris, Arthritis and Immunology Program, 825 that may fulfill these roles have been proposed7 and N.E. 13th Street, Oklahoma City, OK 73104, USA. E-mail: [email protected] include inhibitory receptors such as CTLA-4 and PD-1; Received 27 April 2005; revised 14 June 2005; accepted 15 June 2005; antiproliferative factors such as p27kip1; and E3 ubiqui- published online 21 July 2005 tin ligases, including GRAIL, Itch and c-Cbl. While roles Gene expression of SEB-anergized T cells S Kurella et al 597 for the E3 ubiquitin ligases have been supported by in vivo anergy studies,22,23 both p27kip1 and CTLA-4 have been shown to be nonessential for anergy induction and/or maintenance.24,25 Given the increasingly appre- ciated complexity of the anergic phenotype, the like- lihood that additional unknown anergy factors exist has been recently underscored.7,8 Towards further defining the anergic T-cell state on a molecular basis, this study has demonstrated a number of significant gene expression differences between SEB- anergized CD4 þ Vb8 þ T cells and similarly isolated nonanergic T cells taken from mice that were not exposed to SEB. This is the first report of differential gene expression in the SEB model. In addition to identifying several expression changes previously associated with T- cell anergy, these studies have revealed novel transcrip- tional programs that are likely to affect negatively vital aspects of TCR signal transduction. Moreover, this is the primary report showing association of the Wnt and Notch signaling pathways with T-cell anergy as sug- gested by differential expression of multiple members of these two fundamental pathways that govern cell fate decisions.26,27 Figure 1 Activation of essentially all CD4 þ Vb8 þ T cells in mouse Results spleen 6 h after injection of SEB. BALB/c mice were injected with 50 mg of SEB in PBS (SEB 6 h) or with PBS alone (unstimulated), Generation of anergic T cells by in vivo exposure euthanized 6 h later and their splenocytes evaluated by flow to SEB cytometry. Histograms depicting relative expression levels of The goal of the current study is to determine gene CD69 and CD25 are gated on CD4 þ Vb8 þ lymphocytes. Greater than 95% of CD4 þ Vb8 þ T cells were activated. expression profiles of Tcells made anergic by exposure to the bacterial superantigen SEB. It has previously been established that intraperitoneal immunization of BALB/c cells retained the anergic phenotype, CD4 þ Vb8 þ mice with a bolus of SEB rapidly activates the vast splenic T cells from BALB/c mice that had been injected majority of T cells bearing Vb8 T-cell receptors.5 Follow- 7 days previously with SEB or PBS were sorted, rested ing the death of a subset of these cells at approximately for 3 days in media containing IL-7, then subjected to a 3–4 days postimmunization, surviving SEB-exposed [3H]-thymidine proliferation assay in the presence or CD4 þ Vb8 þ T cells are anergic as defined by a loss of absence of SEB or SEA (Figure 3). CD4 þ Vb8 þ T cells proliferative capacity and ability to secrete IL-2.5,7 To that had been exposed to SEB in vivo remained anergic, validate this well-established model in our laboratory, as evidenced by a lack of proliferation to SEB, while splenic T cells were taken from mice 6 h after injection sorted cells taken from control PBS injected mice with either 50 mg SEB in PBS or with PBS alone and proliferated robustly. Results from restimulation with evaluated for activation marker expression by flow SEA reflect the absence of Vb6 þ T cells in the sorted cytometry. At 6 h postimmunization, over 95% of populations. CD4 þ Vb8 þ T cells expressed CD69, while more than 90% of CD4 þ Vb8 þ T cells expressed CD25 at this time Evaluation of gene expression profiles using point (Figure 1). To evaluate the effectiveness of this microarray chips containing 5184 complementary immunization protocol for inducing T-cell anergy, DNAs (cDNAs) splenic T cells were taken from mice euthanized 7 days We hypothesized that sustained tolerance in SEB- after receiving similar injections of SEB or PBS alone and responsive CD4 þ T cells correlates with a distinct evaluated for in vitro responsiveness to SEB using a genetic program that is likely to be important for standard tritiated thymidine incorporation assay. maintenance of the anergic state. To test this hypothesis, Figure 2a shows that splenic T cells from SEB-immunized gene expression profiles of resting SEB-anergized CD4 þ mice responded poorly to SEB, while T cells from mice Vb8 þ T cells and resting nonanergic CD4 þ Vb8 þ T immunized with PBS alone proliferated robustly. Flow cells were evaluated using cDNA microarrays containing cytometry revealed that the fraction of CD4 þ T cells 5184 cDNAs and ESTs that were not specifically selected expressing Vb8 in SEB- and PBS-immunized mice 7 days for immunological studies. CD4 þ Vb8 þ T cells were postinjection was 21 and 27.5%, respectively (data not isolated from groups of mice injected with either SEB in shown), indicating that deletion of CD4 þ Vb8 þ T cells PBS (anergic T cells) or PBS alone (nonanergic T cells) in SEB-injected mice was only a minor contributor to the using high-speed cell sorting.
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