Release and clinical significance of soluble CD83 in chronic lymphocytic leukemia
Introduction
Chronic lymphocytic leukemia (CLL) is characterised by a variable clinical course and remains largely incurable [1]. The development of more effective treatment strategies requires both a better understanding of the biological factors involved in CLL progression, and the identification of new prognostic factors.
The glycoprotein CD83, which is expressed by activated lymphocytes, dendritic cells (DC) and neutrophils, plays a central role in immunoregulation and is the focus of considerable interest as a therapeutic target [2], [3], [4], [5]. The exact cellular pathways regulated by the interaction of CD83 with its as yet uncharacterised ligand(s) are presently unknown. It is clear however that CD83 plays a critical role in thymic CD4+ T cell development and the involvement of CD83 in increasing not only DC function but also lymphocyte survival, differentiation and immunosuppressive activity has been reported [3], [4], [5], [6], [7], [8].
Human plasma contains a circulating soluble form of CD83 (sCD83) which is also released in low levels by B cells and DC following in vitro activation [9], [10], [11], [12]. Numerous in vitro and in vivo studies have shown that soluble forms of CD83 can suppress a wide range of immune responses including in vivo anti-tumour responses [3], [4], [5], [11], [12], [13], [14], [15]. Alternate transcripts of CD83, some of which encode soluble forms with inhibitory activity, have been identified but little is known regarding their cellular expression [14], [16].
There is increasing evidence that CD83 may have a role in human malignancy. Expression of CD83 by Hodgkin Reed–Sternberg cells and in vitro activated leukemic cells has been reported [16], [17], [18], [19], chromosome alterations in the region of the CD83 gene (6p23) have been reported in lymphoma and cervical cancer [16], [20], [21] and increased CD83 gene expression has been described in some lymphomas and leukemias [22], [23], [24]. A study of invasive cervical cancer also reported that CD83 gene polymorphisms were associated with increased cancer risk and that expression of an alternate transcript, encoding a putative functional sCD83, was significantly more frequent in cancerous tissue [16].
The release of sCD83 provides a potentially powerful mechanism by which APC and/or malignant cells could regulate anti-tumour responses. The report of significantly elevated levels of sCD83 in patients with CLL [9] together with the immunosuppressive activity of sCD83 raises the possibility that sCD83 may play a role in enabling CLL cells to escape immunosurveillance. In order to help clarify the functional and prognostic significance of sCD83 in CLL we analysed (i) the ability the of CLL cells to release sCD83 (ii) the expression of alternate CD83 transcripts by CLL cells and (iii) the prognostic significance of plasma sCD83 levels in CLL patients.
Section snippets
Reagents
The isotype control antibodies were obtained from Sigma (St. Louis, MO) and PE conjugated sheep anti-mouse Ig (PE-SAM) was obtained from Chemicon Australia (Melbourne, Australia). The mAb HB15a (CD83) and PE conjugated CD38 mAb (IO test) were obtained from Beckman Coulter (Miami, Florida, USA). All other mAb were produced in the laboratory as described previously [25].
sCD83, IL-10, IL-6, VEGF, MMP-9 ELISA's
Levels of sCD83 were measured using a modification of our previously described ELISA [9]. Modifications were the use of 10% goat
Release of sCD83 by CLL cells and normal donor PBMC
We have reported previously that solid phase (sp) CD40 (spCD40) mAb can induce the release of soluble CD40 (sCD40) by CLL cells and additional studies have reported that spCD40 plus IL-4, can upregulate mCD83 expression by CLL cells [19], [25]. Therefore the effects of spCD40 mAb, spCD83 mAb and IL-4 on sCD83 release by CLL cells was analysed (Fig. 1a). CLL cells cultured in the presence of solid phase control or CD40 mAb released only low levels of sCD83 (<150 pg/ml) even in the presence of
Discussion
Soluble forms of CD83 have been shown to have potent immunosuppressive activity [3], [4], [5] and, in the context of malignancy, sCD83 release has the potential to suppress not only anti-tumour responses but also normal T cell development. The finding in this study that CLL cells upregulate generation of both mCD83 and sCD83 following activation suggests CD83 may play a role in CLL biology.
Increased expression of mCD83 by CLL cells in response to IL-4 was not associated with increased release
Conflict of interest
The authors have no financial interests.
Acknowledgements
Supported by grants from the Maurice & Phyllis Paykel Trust, Leukemia and Blood Foundation of New Zealand and the Bone Marrow Cancer Research Trust. A.S. was supported by the Deutsche Forschungsgemeinschaft SFB643, Grant B9 and Grant STE 432/5-1. We wish to thank the volunteers and patients who donated blood samples. We acknowledge the contribution of clinical and laboratory staff of the Haematology Department, Christchurch Hospital in collecting patient samples and information.
Contributions.
References (39)
- et al.
CD83 regulates lymphocyte maturation, activation and homeostasis
Trends Immunol
(2008) - et al.
Dendritic cell CD83: a therapeutic target or innocent bystander?
Immunol Lett
(2008) - et al.
CD83 expression influences CD4+ T cell development in the thymus
Cell
(2002) - et al.
The soluble form of CD83 is present at elevated levels in a number of hematological malignancies
Leuk Res
(2004) - et al.
Infection of mature monocyte-derived dendritic cells with human cytomegalovirus inhibits stimulation of T-cell proliferation via the release of soluble CD83
Blood
(2004) - et al.
Local secretion/shedding of tumor-derived CD83 molecules as a novel tumor escape mechanism
Mol Immunol
(2008) - et al.
Hodgkin's cells express CD83, a dendritic cell lineage associated antigen
Pathology
(1997) - et al.
Inversions of chromosomes 2 and 6 in mantle cell lymphoma. Cytogenetic, FISH, and molecular studies
Cancer Genet Cytogenet
(2006) - et al.
Overexpression, purification, and biochemical characterization of the extracellular human CD83 domain and generation of monoclonal antibodies
Protein Expr Purif
(2002) - et al.
Engagement of CD83 ligand induces prolonged expansion of CD8+ T cells and preferential enrichment for antigen specificity
Blood
(2006)