Response to Comment on ''A Novel Thymoma-Associated Immunodeficiency with Increased Naive T Cells and Reduced CD247 Expression'' This information is current as of October 1, 2021. Paul Fisch, Petros Christopoulos, Alexander Marx and Wolfgang W. A. Schamel J Immunol 2015; 195:3505-3506; ; doi: 10.4049/jimmunol.1501787

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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 © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Letters to the Editor Immunology

Response to Comment on “A Novel due to posttranslational modifications, such as nitration (8), Thymoma-Associated oxidation (2), or cleavage (9), the anti-CD247 Abs might not Immunodeficiency with Increased recognize the modified CD247 chains. Modified CD247 mole- cules might not be able to be phosphorylated at the ITAM Naive T Cells and Reduced CD247 tyrosines, or they might inhibit the CD3 conformational change Expression” that is required for TCR triggering (10). In conclusion, increased blood levels of naive T cells with an impaired ability to secrete INF-g and reduced detection of CD247 in Western blotting may explain the increased risk of e thank Dr. Welch and Dr. Howard for their thymoma patients to develop secondary cancers. How mod- comments on our recent study (1). CD247, ified CD247 expression causes T cells to be less responsive to W a subunit of the TCRab and TCRgd, is often TCR stimuli could be relevant for risk assessment and im- downmodulated in effector and memory T cells in animals munotherapy of cancer and chronic inflammatory diseases, and patients with chronic inflammatory conditions such as when trying to uncover the molecular mechanisms involved. autoimmune and infectious diseases, as well as cancer (2). Our Downloaded from study showed that CD247 can also be downmodulated in Paul Fisch,* Petros Christopoulos,† Alexander Marx,‡ naive T cells of some thymoma patients with myasthenia x { gravis (MG) who show increased numbers of naive T cells in and Wolfgang W. A. Schamel , the peripheral blood (3). In our index patient, markedly in- *Department of Pathology, University of Freiburg Medical Center, 79106 Freiburg, creased gd T cells with Gaussian distributed CDR3 lengths of † Germany; Department of Thoracic Oncology, Thoraxklinik at Heidelberg University http://www.jimmunol.org/ all variable segments revealed that the majority of his Hospital, 69126 Heidelberg, Germany; ‡Institute of Pathology, University Medical Center x peripheral blood T cells were naive. Reduced CD247 ex- Mannheim, University of Heidelberg, 68167 Mannheim, Germany; Department of Molecular Immunology, BIOSS Centre for Biological Signaling Studies, Faculty of { pression correlated with a lower secretion of INFg and IL-2 Biology, University of Freiburg, 79104 Freiburg, Germany; and Center for Chronic upon TCR triggering. We favor the explanation that reduced Immunodeficiency, University of Freiburg Medical Center, 79104 Freiburg, Germany CD247 expression is caused by disturbed T-cell development Address correspondence and reprint requests to Prof. Paul Fisch, Department of Pathology, University of Freiburg Medical Center, Breisacher Strasse 115a, 79106 in some thymomas with increased release of naive, hypo- Freiburg, Germany. E-mail address: paul.fi[email protected] functional T cells into the periphery. In fact, attenuated TCR Abbreviation used in this article: MG, myasthenia gravis. signaling inside MG-associated thymomas might be a pre-

requisite for developing T cells to escape negative T cell se- by guest on October 1, 2021 lection, get exported to the periphery, and largely replace the References functionally competent and tolerant T cell repertoire (3, 4). 1. Christopoulos, P., E. P. Dopfer, M. Malkovsky, P. R. Esser, H.-E. Schaefer, low A. Marx, S. Kock, N. Rupp, M. R. Lorenz, K. Schwarz, et al. 2015. A novel Taking the naive phenotype of the CD247 T cells into thymoma-associated immunodeficiency with increased naive T cells and reduced account, the alternative possibility that CD247 reduction in CD247 expression. J. Immunol. 194: 3045–3053. 2. Baniyash, M. 2004. TCR zeta-chain downregulation: curtailing an excessive thymocytes and peripheral T cells in some thymoma patients inflammatory immune response. Nat. Rev. Immunol. 4: 675–687. could be secondary to malignancy and chronic inflammation 3. Buckley, C., D. Douek, J. Newsom-Davis, A. Vincent, and N. Willcox. 2001. appears less likely. Since thymoma-derived, intrinsically hypo- Mature, long-lived CD41 and CD81 T cells are generated by the thymoma in myasthenia gravis. Ann. Neurol. 50: 64–72. reactive T cells might compromise immune surveillance, we 4. Stro¨bel, P., M. Helmreich, G. Menioudakis, S. R. Lewin, T. Rudiger,€ A. Bauer, agree with Drs. Welch and Howard that reduced CD247 ex- V. Hoffacker, R. Gold, W. Nix, B. Schalke, et al. 2002. Paraneoplastic myas- thenia gravis correlates with generation of mature naive CD4(1) T cells in pression might contribute to the increased rate of secondary thymomas. Blood 100: 159–166. malignancies in thymomas (5), predominantly observed in 5. Souadjian, J. V., M. N. Silverstein, and J. L. Titus. 1968. Thymoma and cancer. Cancer 22: 1221–1225. patients with cortical thymomas (6) such as our cases. 6. Granato, F., V. Blackhall, R. Alessandra, D. Spina, V. Luca, P. Piero, How reduced CD247 expression dampens T-cell responses S. Mohiyaddin, M. Asif, A. J. Kirk, and G. Giuseppe. 2014. Outcome in excised thymomas: role of prognostic factors and impact of additional malignancies on remains unclear, since the amount of TCRs present on the cell survival. Scott. Med. J. 59: 22–29. surface appears unchanged (2). There are two possibilities: 7. Sussman, J. J., J. S. Bonifacino, J. Lippincott-Schwartz, A. M. Weissman, T. Saito, 1) In the absence of CD247, the partially assembled TCRs do R. D. Klausner, and J. D. Ashwell. 1988. Failure to synthesize the T cell CD3-zeta chain: structure and function of a partial T cell complex. Cell 52: 85–95. not reach the cell surface (7). Thus, in TCRs without CD247 8. Nagaraj, S., A. G. Schrum, H. I. Cho, E. Celis, and D. I. Gabrilovich. 2010. surface expression, another subunit such as the FcRg-chain Mechanism of T cell tolerance induced by myeloid-derived suppressor cells. J. Immunol. 184: 3106–3116. could substitute for CD247 (2). Since the signaling potential 9. Hanaoka, N., B. Jabri, Z. Dai, C. Ciszewski, A. M. Stevens, C. Yee, of FcRg, containing one ITAM, is lower than that of CD247 H. Nakakuma, T. Spies, and V. Groh. 2010. NKG2D initiates caspase-mediated CD3zeta degradation and lymphocyte receptor impairments associated with containing three ITAMs, this may lower the capacity of T-cell human cancer and autoimmune disease. J. Immunol. 185: 5732–5742. activation. 2) CD247 might be expressed at normal levels, but 10. Minguet, S., M. Swamy, B. Alarco´n, I. F. Luescher, and W. W. Schamel. 2007. Full activation of the T cell receptor requires both clustering and conformational changes at CD3. Immunity 26: 43–54. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1501787