The Low Affinity Fc Receptor for IgG Functions as an Effective Cytolytic Receptor for Self-Specific CD8 T Cells This information is current as Salim Dhanji, Kathy Tse and Hung-Sia Teh of September 28, 2021. J Immunol 2005; 174:1253-1258; ; doi: 10.4049/jimmunol.174.3.1253 http://www.jimmunol.org/content/174/3/1253 Downloaded from References This article cites 24 articles, 11 of which you can access for free at: http://www.jimmunol.org/content/174/3/1253.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 28, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology The Low Affinity Fc Receptor for IgG Functions as an Effective Cytolytic Receptor for Self-Specific CD8 T Cells1 Salim Dhanji, Kathy Tse, and Hung-Sia Teh2 We have recently described a population of self-Ag-specific murine CD8؉ T cells with a memory phenotype that use receptors of both the adaptive and innate immune systems in the detection of transformed and infected cells. In this study we show that upon activation with IL-2 with or without Ag, between 10 and 20% of the activated self-specific CD8؉ T cells express the low affinity FcR for IgG. By contrast, all IL-2-activated NK cells express high levels of this FcR. The FcR comprises the Fc␥RIII␣ and FcR␥ subunits. However, the FcR␥ subunit also associates with the CD3 complex, and this association probably contributes to the low expression of FcR in activated cells. Although the FcR is expressed at a low level on activated self-specific CD8؉ T cells, it functions very efficiently as a cytolytic receptor in ADCC. FcR-dependent killing occurred in the absence of TCR stimulation, but could be ؉ augmented by concurrent stimulation of the TCR. In addition to mediating ADCC, engagement of the FcR on self-specific CD8 Downloaded from T cells results in the production of both IFN-␥ and TNF-␣. This is the first report of an activating FcR on self-specific murine CD8؉␣␤ TCR؉ T cells and establishes the importance of innate immune system receptors in the function of these self-specific .CD8؉ T cells. The Journal of Immunology, 2005, 174: 1253–1258 atural killer cells represent a highly specialized lym- Fc␥RIII␣ associates mainly with ITAM-containing homo- or het- ␨ ⑀ ␥ ␥ phoid population characterized by potent cytolytic ac- erodimers of CD3 and Fc RI (FcR ) in humans (8) or solely http://www.jimmunol.org/ N tivity against tumor or virally infected cells. Their func- with FcR␥ homodimers in mice (9). The binding of IgG to CD16 tion is finely regulated by a series of inhibitory or activating results in the phosphorylation of ITAMs in the signaling chains, receptors (1). The inhibitory receptors, specific for MHC class I leading to the recruitment of kinases such as ZAP-70 and Syk (10). molecules, allow NK cells to discriminate between normal cells These kinases initiate a signaling cascade resulting in the lysis of and cells that have lost the expression of MHC class I (e.g., tumor Ab-coated target cells. T cells also use ITAM-containing receptors cells). Inhibitory receptors, such as those belonging to the Ly49 and Syk and ZAP-70 for their signal transduction (reviewed in Ref. family in mice and the killer Ig-like receptors in humans, contain 11). Thus, the signals transduced by the engagement of CD16 on ITIM motifs in their cytoplasmic domains (2). Engagement of NK cells are very similar to those transduced by the engagement of these receptors results in the recruitment of inhibitory phospha- TCR on T cells. by guest on September 28, 2021 tases that prevent NK cell activation. The activating receptors re- CD16 expression is not limited to NK cells; other cell types sponsible for NK cell triggering include NKp46, NKp30, NKp44, have been described that also express this receptor. ␥␦ T cells have and NKG2D in humans and NKp46 and NKG2D in mice (3, 4). been shown to express CD16, as have a population of large gran- The activating receptors, some of which belong to the same fam- ϩ Ϫ Ϫ ular lymphocytes (mostly ␣␤TCR CD4 CD8 T cells) in hu- ilies, do not contain activation motifs, but, rather, associate with mans (12, 13). In addition, some memory phenotype adaptor molecules or signaling partners important for signal trans- ␣␤TCRϩCD8ϩ T cells in humans have been shown to express duction (5). CD16 (14). We have previously described a population of One of the first activating receptors described on NK cells is ␣␤ ϩ ␣␤ϩ Fc␥RIII␣ or CD16. CD16 is a low affinity FcR that binds to IgG TCR CD8 T cells in normal B6 mice that exhibit a mem- and is involved in Ab-dependent cell-mediated cytotoxicity ory phenotype characterized by the expression of high levels of ␤ (ADCC),3 in which an Ab-coated target cell is destroyed by NK CD44, IL-2R , and Ly6C (15). These cells can be activated by cells (6). Stimulation of CD16 on NK cells also results in the cytokines such as IL-2 and IL-15, and upon activation they express production of cytokines, such as IFN-␥, TNF-␣, and GM-CSF (7). several functional NK receptors, including 2B4, CD94, and NKG2D as well as the NK adaptor protein DAP12. Using an H-Y TCR transgenic model, we have shown that the development of CD8ϩCD44high T cells is driven by the high affinity interaction of Department of Microbiology and Immunology, University of British Columbia, Van- couver, Canada the ␣␤TCR with cognate self-Ag (16). The H-Y TCR is specific b b Received for publication May 7, 2004. Accepted for publication November 9, 2004. for a male Ag (H-Y) presented by H-2D , and in H-2 H-Y female The costs of publication of this article were defrayed in part by the payment of page mice, the lack of male Ag results in the development of H-Y CD8 charges. This article must therefore be hereby marked advertisement in accordance T cells with a naive phenotype (CD44low). In H-2b H-Y male mice, with 18 U.S.C. Section 1734 solely to indicate this fact. in contrast, the presence of the cognate (H-Y) Ag results in the 1 This work was supported by grants from the Canadian Cancer Society and the development of a population of CD8ϩ T cells that is virtually Canadian Institutes of Health Research (to H.S.T.). S.D. is supported by the Natural Sciences and Engineering Research Council of Canada and the Michael Smith Foun- identical in cell surface and functional phenotypes with the mem- dation of Health Research. ory phenotype CD8ϩCD44high cells in normal B6 mice (16). Be- 2 Address correspondence and reprint requests to Dr. Hung-Sia Teh, Department of cause memory phenotype CD8ϩ T cells in normal and H-Y TCR Microbiology and Immunology, University of British Columbia, 6174 University Boulevard, Vancouver, British Columbia, Canada V6T 1Z3. E-mail address: transgenic mice are specific for self-Ags, we will refer to these ϩ [email protected] cells as self-specific CD8 T cells to distinguish them from con- ϩ ϩ 3 Abbreviations used in this paper: ADCC, Ab-dependent cell-mediated cytotoxicity. ventional memory CD8 T cells. Self-specific CD8 T cells from Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 1254 SELF-SPECIFIC CD8ϩ T CELLS EXPRESS AN ACTIVATING FcR both H-Y TCR transgenic (16) and nontransgenic (15) mice pref- sciences). CD3 immunoprecipitation was preformed by treating lysates erentially kill syngeneic tumor cells. This killing of syngenic tu- with preconjugated anti-CD3⑀/protein G-Sepharose beads for2hat4°C, mors involves the MHC-restricted ␣␤ TCR as well as the activat- followed by several washes. Complexes were then removed from the beads by resuspension in 2ϫ protein sample buffer, followed by boiling for 5 ing NK receptor, NKG2D, which results in non-MHC-restricted min. The samples were then run in a 4–15% Tris-HCl gel and immuno- lysis of target cells that express the NKG2D ligand, Rae-1 (16). blotted as described above. In this report we have described the expression and function of CD16 in self-specific CD8ϩ cells from B6 and male H-Y TCR Results transgenic mice. We showed that this FcR, comprising the Expression of Fc␥RIII␣/FcR␥ on activated self-specific Fc␥RIII␣/FcR␥ subunits, is similar in composition to the NK FcR. CD8ϩ cells Although this FcR is expressed at a low level in self-Ag-specific ϩ ϩ We have previously shown that self-specific CD8 T cells express CD8 T cells, it is particularly efficient at initiating the destruction an activated/memory phenotype (15, 16). Initially, ex vivo self- of Ab-coated target cells and can induce the production of two key specific CD8ϩ cells from B6 and male H-2b H-Y mice did not ␥ ␣ inflammatory cytokines, IFN- and TNF- .