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And Cytokine Production T Cell Proliferation + Antigen-Specific Ly-6A.2 Expression Regulates Antigen-Specific CD4؉ T Cell Proliferation and Cytokine Production1 S. Christine Henderson, Mihir M. Kamdar, and Anil Bamezai2 Ly-6 proteins appear to serve cell adhesion and cell signaling function, but the precise role of Ly-6A.2 in CD4؉ T lymphocytes is still unclear. Overexpression of Ly-6A.2 in T lymphocytes has allowed us to analyze the influence of elevated Ly-6A.2 expression on T cell function. In this study we report reduced proliferation of CD4؉ T cells overexpressing Ly-6A.2 in response to a peptide -Ag. Moreover, the Ly-6A.2-overexpressing CD4؉ cells generated elevated levels of IL-4, a key factor that propels the differen tiation of naive CD4؉ T cells into Th2 subset. The hyporesponsiveness of Ly-6A.2 transgenic CD4؉ T cells is dependent on the interaction of Ly-6A.2 T cells with the APCs and can be reversed by blocking the interaction between Ly-6A.2 and a recently reported candidate ligand. Overexpression of Ly-6A.2 in CD4؉ T cells reduced their Ca2؉ responses to TCR stimulation, therefore suggesting effects of Ly-6A.2 signaling on membrane proximal activation events. In contrast to the observed Ag-specific hypore- sponsiveness, the Ly-6A.2 transgenic CD4؉ T cells produced IL-4 independent of the interactions between Ly-6A.2 and the candidate Ly-6A.2 ligand. Our results suggest that 1) interaction of Ly-6A.2 with a candidate ligand regulates clonal expansion of CD4؉ Th cells in response to an Ag (these results also provide further functional evidence for presence of Ly-6A.2 ligand on APC); and 2) Ly-6A.2 expression on CD4؉ T cells promotes production of IL-4, a Th2 differentiation factor. The Journal of Immunology, 2002, 168: 118–126. rowth and differentiation of T cells following an encoun- these cytokines (e.g., IL-2) play a central role in clonal expansion, ter with an Ag are critical for proper immune function. whereas other cytokines produced influence differentiation of na- G The specificity of the clonal expansion and differentia- ive CD4ϩ T cells into either Th1 (IFN-␥) or Th2 (IL-4) subset tion of lymphocytes are determined by the interaction of TCR with (reviewed in Refs. 12 and 13). Therefore, understanding the influ- its ligand, a peptide-MHC complex expressed on the APCs. Clonal ence of accessory proteins on naive or activated CD4ϩ T cells in expansion of CD4ϩ T cells is tightly regulated, as unchecked generation of cytokines (type and quantity) that direct T cell dif- growth can cause toxic effector functions and unbalanced immune ferentiation is critical, especially when cytokine-induced differen- responses to foreign Ags. Although the mechanism of regulation of tiation can determine the kind of immune response generated T cell growth remains largely unknown, previous studies suggest against a pathogen or allergen (reviewed in Refs. 14–17). The role that surface expression of CTLA-4, Fas/APO-1, IL-2R proteins of accessory molecules expressed on naive or activated T cells in may regulate CD4ϩ T cell growth (1–3). Mice lacking expression generation of cytokines that in turn influence T cell differentiation of CTLA-4, Fas, or IL-2R show lymphoproliferation and abnormal remains unresolved. accumulation of activated T cells, suggesting their importance in The mouse Ly-6 locus encodes a family of GPI-anchored, de- regulating homeostasis of either naive and/or cycling T cells (4–7). velopmentally regulated cell surface proteins (reviewed in Refs. 18 Moreover, single gene mutations of Cbl, SLP, HPK1, and Csk in and 19). Members of Ly-6 gene family are excellent markers of mice are known to cause hyperproliferation of T cells and there- different lineages of hemopoietic origin, including lymphocytes fore suggest a role of these kinases in inhibiting T cell stimulation (20–25), monocytes (26, 27), bone marrow cells (20, 27, 28), and (8–11). The cell surface proteins that regulate these intracellular granulocytes (29). There are shared motifs among the mouse Ly-6 kinases have not been identified. Many of these regulatory mole- proteins, including 8–10 conserved cysteine residues which are cules or growth inhibitory pathways may function in different T also found in human CD59, epidermal growth factor, urokinase cell subsets or at different stages of clonal expansion or even work plasminogen activator receptor, squid Sgp-2, SP-10 (sperm Ag) synergistically. Mechanisms underlying these intricate regulations (reviewed in Ref. 30), snake neurotoxins/cytotoxins (29), and Cae- of clonal expansion following an encounter with foreign Ag re- norhabditis elegans odr-2 (31). All these proteins from different mains unclear. species have been grouped together into Ly-6 supergene family ϩ Stimulation of CD4 T cells with Ag initiates production of a based on their limited amino acid similarity and the presence of variety of cytokines including IL-2, IFN-␥, and IL-4. Some of conserved cysteine residues. Published reports have suggested role of Ly-6 protein in T cell signaling (32, 33) and cell adhesion (34– 36). Surface expression of Ly-6A.2 is important for immunore- Department of Cellular Biology, University of Georgia, Athens, GA 30602 sponsiveness of both T-T hybridomas (37) and normal T cells (38). Received for publication June 21, 2001. Accepted for publication October 25, 2001. Interestingly, surface expression of TCR/CD3 expression on T-T The costs of publication of this article were defrayed in part by the payment of page hybridomas is important for stimulation through the Ly-6 protein charges. This article must therefore be hereby marked advertisement in accordance (39, 40). Moreover, ectopic expression of Ly-6A.2 transgene on with 18 U.S.C. Section 1734 solely to indicate this fact. CD4ϩCD8ϩ thymocytes promotes maturation of CD4ϩ (not 1 This work was supported by Research Project Grant RPG-97-089-01-CIM from the CD8ϩ) T cells in the thymus in the absence of TCR-MHC inter- American Cancer Society (to A.B.). action (41). These data suggest that Ly-6A.2 expression influences 2 Address correspondence and reprint requests to Dr. Anil Bamezai, Department of Cellular Biology, University of Georgia, 724 Biological Sciences Building, Athens, cell growth and differentiation that are dependent or independent GA 30602. E-mail address: [email protected] of signaling through the Ag receptor. Contrary to some published Copyright © 2002 by The American Association of Immunologists 0022-1767/02/$02.00 The Journal of Immunology 119 reports, the CD4ϩ T cells from Ly-6A mutant mice show a mod- Cell preparation estly higher proliferation in response to anti-CD3 Ab than their CD4ϩ T cells from Ly-6A.2 Tg or non-Tg mice were prepared from the controls (42). Moreover, Abs against Ly-6A.2 inhibit anti-CD3- lymph nodes. Lymph node cells were incubated with 100 ␮l of anti-CD8 induced IL-2 production by T-T hybridoma (43). The role of Ly- (3.155) and anti-MHC class II (M5/114) Abs for 30 min at 4°C. Samples 6A.2 expression in Ag-specific response of primary CD4ϩ T cells were washed three times with the PBS supplemented with 0.1% BSA. remains untested and the mechanism by which Ly-6A.2 expression Following the washing step, cells were incubated with Dynal beads M-450 coupled with sheep anti-mouse IgG Ab, as per the manufacturer’s instruc- may augment or inhibit the TCR-induced activation is unknown. tions (Dynal Biotech, Oslo, Norway) for 45 min at 4°C. Depletion of con- Ly-6A.2 and other members of the Ly-6 gene family, including taminating cells was achieved by magnetic separation, and purity of CD4ϩ E48 protein and Ly-6C, participate in cell-cell adhesion (35, 36). cells ranged from 85 to 95%. We recently reported biochemical characterization of a candidate Flow cytometry ligand that binds Ly-6A.2 (44). The Ly-6A.2 candidate ligand is ϫ 6 ϩ expressed on the majority of B cells and macrophages (Refs. 34 A total of 1 10 lymph node or purified CD4 cells were incubated with anti-CD4-PE, anti-CD8-FITC, anti-Ly-6A/E (D7) (BD PharMingen, San and 44 and our unpublished data). Moreover, a ligand for Ly-6 day Diego, CA), and anti-DO11 TCR (KJ1-26) (49) Abs followed by appro- (Ly-6dL), another member of the Ly-6 gene family, was recently priate fluorochrome-conjugated second step reagents. Cells were analyzed identified that shows expression in almost all mouse tissues ana- on an EPICS Elite Analyzer flow cytometer (Beckman Coulter, lyzed (45). Ly-6dL shows similarity to epidermal growth factor Fullerton, CA). domain of mouse notch (motch-1) protein, known for its role in ELISA for detection of anti-DNA Abs and cytokines directing cell fate decisions in a variety of cell types during de- For detection of anti-DNA Abs, the microtiter wells were coated with velopment (reviewed in Ref. 46). These observations raise the pos- poly-L-lysine (25 ␮g/ml) for 24 h at 4°C. Excess of poly-L-lysine was sibility that Ly-6 proteins may mediate cell function by binding to removed by washing with 0.1 M TBS containing 0.1% Tween 20 before a ligand, but the consequences of these Ly-6-ligand interactions coating of dsDNA at 5 ␮g/ml for2hatroom temperature (RT). Sera from are unknown. mice were analyzed at 1/10, 1/100, and 1/1000 dilution by incubating for 60 min at RT. The presence of anti-dsDNA Abs was detected by incubation To examine the role of Ly-6A.2 expression on the function of ϩ with protein G-alkaline phosphatase at 1/4000 dilution for1hatRTand CD4 T cells, we bred the Ly-6A.2 transgenic (Tg)3 mice with the assay was developed in the presence of the substrate, p-nitrophenyl DO11 TCR-Tg mice.
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