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CS1 (CRACC, CD319) Induces Proliferation and Autocrine Cytokine Expression on Human B Lymphocytes¹

Jae Kyung Lee^*, Stephen O. Mathew, Swapnil V. Vaidya, Pappanaicken R. Kumaresan and Porunelloor A. Mathew^2,

^* Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390; Department of Molecular Biology and Immunology and Institute for Cancer Research, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107; Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205; and Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis Cancer Center, University of California Davis Medical Center at Sacramento, CA 95817

CS1 (CRACC, CD319), a member of the CD2 family of cell surface receptors, is implicated in the activation of NK cell-mediated cytotoxicity. Previous studies showed that CS1 is also expressed on activated B cells. However, the functional role of CS1 in human B-lymphocytes is not known. Two isoforms of CS1, CS1-L and CS1-S, are expressed in human NK cells that differentially regulate NK cell function. CS1-L contains immunoreceptor tyrosine-based switch motifs in its cytoplasmic domain whereas CS1-S lacks immunoreceptor tyrosine-based switch motifs. In this study, we show that human B lymphocytes express only the CS1-L isoform, and its expression is up-regulated upon B cell activation with various stimulators. Moreover, anti-CS1 mAb strongly enhanced proliferation of both freshly isolated as well as activated B cells. The enhanced proliferation effects of CS1 were most prominent on B cells activated by anti-CD40 mAbs and/or hrIL-4. The effects of CS1 on B cell proliferation were shown on both naive and memory B cells. Human cytokine microarray and quantitative real-time PCR results indicated that CS1 activation enhanced mRNA transcripts of flt3 ligand, lymphotoxin A, TNF, and IL-14. Neutralizing Abs against lymphotoxin A, TNF-, and/or flt3 ligand abolished the ability of CS1 on the B cell proliferation. These results suggest that activation of B lymphocytes, through surface CS1, may be mediated through secretion of autocrine cytokines and CS1 may play a role in the regulation of B lymphocyte proliferation during immune responses.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant CA85753.

² Address correspondence and reprint requests to Dr. Porunelloor Mathew, Department of Molecular Biology and Immunology, University of North Texas Health Science Center at Fort Worth, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699. E-mail address: pmathew{at}hsc.unt.edu

³ Abbreviations used in this paper: SLAM, signaling lymphocytic activation molecule; ITSM, immunoreceptor tyrosine-based switch motifs; SAP, SLAM-associated protein; EAT-2, EWS-activated transcript-2; hr, human recombinant; RT, reverse transcriptase; LTA, lymphotoxin-; flt3L, flt3 ligand; TNFSF13B, TNF superfamily factor 13B; NHL, non-Hodgkin’s lymphoma.