CD38 expressed on human monocytes: A coaccessory molecule in the superantigen-induced proliferation

Self Cite

125

The absence of mutations in the IgV genes, together with the presence of ZAP-70 and CD38, are the most reliable negative prognostic markers for chronic lymphocytic leukemia (CLL) patients. Several lines of evidence indicate that CD38 may be not only a diagnostic marker but also a key element in the pathogenetic network in CLL. First, CD38 is a receptor that induces proliferation and increases survival of CLL cells. Second, CD38 signals start upon interaction with the CD31 ligand expressed by stromal and nurselike cells. Third, CD38/CD31 contacts upregulate CD100, a semaphorin involved in sustaining CLL growth. Fourth, evidence that nurselike cells express high levels of CD31 and plexin-B1, the high-affinity ligand for CD100, offers indirect confirmation for this model of receptor cross-talk. IntroductionChronic lymphocytic leukemia (CLL) is defined as a proliferation of B lymphocytes that express surface CD19 or CD20, CD5, CD23, and low levels of immunoglobulin (Ig), CD79␤, and CD22. 1 CLL is a heterogeneous disease: some patients experience a slowly progressive clinical course but most will eventually enter an advanced phase and require recurrent treatment. A significant number of CLL patients show an active form of the disease from the early stages, characterized by refractoriness to treatment, infectious and autoimmune complications, and a relatively rapid fatal outcome. 2 Unlike most other B-lymphoproliferative disorders, little is known about the pathogenesis of CLL. The main challenge lies in determining the cellular origin of the disease and, consequently, the degree of immunocompetence of CLL cells. However, no common key cytogenetic abnormalities have been identified that might otherwise offer pathogenetic clues. 3,4 Heterogeneity in the clinical behavior of CLL makes it difficult to identify which patients will benefit most from earlier or more aggressive treatment and those who should be treated with more conservative and less toxic approaches. Clinical researchers have long sought to identify a marker (or markers) for use as a prognostic tool. 5 The earliest staging systems for CLL relied on disease burden parameters. The Rai and Binet systems were the first to determine a correlation between survival and different measures of disease burden. 6,7 Histologic patterns of bone marrow (BM) involvement have also been used as a valid adjunct. 8 However, these classifications fail to distinguish patients who will eventually progress to an aggressive form of the disease from those who have a more stable form. Likewise, lymphocyte doubling time (LDT), which is calculated by determining the number of months it takes the absolute lymphocyte count to double, shares the same drawback. Although it offers meaningful evidence about disease kinetics 9 and is therefore widely used as a measure of disease aggressiveness, treatment decisions based solely on LDT may come too late for patients who eventually prove to have aggressive forms of the disease.During the past 15 years, several soluble molecules have been used a...

Section: Functionsmentioning

confidence: 99%

Section: Structurementioning

confidence: 99%

In-tandem insight from basic science combined with clinical research: CD38 as both marker and key component of the pathogenetic network underlying chronic lymphocytic leukemia

Deaglio¹,

Vaisitti²,

Aydin³

et al. 2006

Self Cite

125

“…[1][2][3] Aside from its ectoenzymatic activities and, apparently with independent modalities, CD38 may perform as a receptor, ruling adhesion and signaling in T 4 and B lymphocytes, 5 monocytes, 6 and natural killer (NK) cells. 7,8 The receptor functions of CD38 are regulated through interaction with a counterreceptor, identified as CD31.…”

Section: Introductionmentioning

confidence: 99%

Human CD38 and CD16 are functionally dependent and physically associated in natural killer cells

Deaglio

Zubiaur²,

Gregorini³

et al. 2002

107

IntroductionHuman CD38 is the prototype of a family of proteins that share structural similarities and ectoenzymatic activities involved in the production of calcium-mobilizing compounds. [1][2][3] Aside from its ectoenzymatic activities and, apparently with independent modalities, CD38 may perform as a receptor, ruling adhesion and signaling in T 4 and B lymphocytes, 5 monocytes, 6 and natural killer (NK) cells. 7,8 The receptor functions of CD38 are regulated through interaction with a counterreceptor, identified as CD31. 9 The signaling events initiated by interactions between CD38 and CD31 (and fully mimicked by agonistic anti-CD38 monoclonal antibodies [mAbs]) were initially studied in the dynamic context of circulating CD38 ϩ T lymphocytes adhering to CD31 ϩ endothelial cells. 10 Use of this model allowed definition of some of the events that take place after the interaction and that include calcium (Ca ϩϩ ) mobilization from cytosolic stores, tyrosine phosphorylation of selected substrates, activation of nuclear factors, and secretion of cytokines. 11 It is generally agreed that CD38 controls a specific signaling pathway in T cells, B cells, NK cells, and monocytes. In spite of this evidence, the modalities through which the signal is initiated remain elusive. The molecule has neither the canonical structure of a receptor nor the hallmark domains. Indeed, the cytoplasmic tail is short and lacks docking sites and it is not tyrosine phosphorylated on activation. 12,13 Such negative characteristics are even more evident in CD157, the other member of the protein family, whose signaling features are known, notwithstanding a glycophosphatidylinositol linkage to the cell membrane. 14,15 Some clues can be extrapolated from cocapping experiments, which show that CD38 associates on the cell membrane with professional signaling receptors such as the T-cell receptor (TCR)-CD3 complex in T cells, the B-cell receptor (BCR) in B cells, and CD16 in NK cells. 16 A hypothesis to explain the signaling properties of CD38 is that the molecule exploits the signaling machinery of professional receptors to deliver its own independent signals. This idea was first supported by experiments using CD38 ϩ T-cell lines deficient in components of the signaling apparatus of the TCR-CD3 complex. 17,18 The inability of CD38 to signal in these cells was overcome by reconstituting a complete TCR-CD3 complex, thereby indicating that CD38 signaling depends on the presence of a functional TCR. These observations were recently expanded by studies using T lymphocytes purified from the intestinal The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 U.S.C. section 1734. For personal use only. on May 11, 2018. by guest www.bloodjournal.org From lamina propria as a model in which the TCR complex is physiologically impaired. 19 A comparative analysis of circulating versus residential T lymphocytes from the s...

“…[12][13][14] CD38 establishes associations with distinct surface molecules, which vary according to cell lineage. In monocytes CD38 shares with HLA class II and CD9 a common activation pathway, 15 and the association is implemented before monocytes interact with T lymphocytes. 16 Dynamic changes in these molecular associations, such as recruitment of other surface and/or signaling molecules, may occur during the formation and establishment of the relevant synapses.…”

mentioning

confidence: 99%

Antigen-induced clustering of surface CD38 and recruitment of intracellular CD38 to the immunologic synapse

Muñoz

Mittelbrunn

Fuente

et al. 2008

Self Cite

CD38 is a cell-surface molecule, highly conserved in phylogeny and not restricted to a lineage or a differentiation step. The molecule is functionally pleiotropic in that it features as an ectoenzyme and simultaneously as a receptor. 2 The extracellular domain of CD38 catalyzes the synthesis of cADPR and nicotinic acid adenine dinucleotide phosphate (NAADP) from NAD ϩ and NADP ϩ , respectively. cADPR is a universal second messenger that can control Ca 2ϩ levels in an IP3-independent way. ADPR and NAADP produced by CD38 also cooperate in the regulation and modulation of intracellular Ca 2ϩ . [3][4][5][6] The role of CD38 as a receptor was first identified by means of agonistic monoclonal antibodies (mAbs), which anticipated the existence of a nonsubstrate surface ligand, namely CD31/PECAM-1. 7 CD38 signaling in T cells is functionally dependent on the TCR/CD3 complex, 8,9 and it is initiated in a subset of membrane rafts containing CD38, Lck, and the CD3-chain of the TCR. 10,11 As Lck and CD3-molecules are recruited to the IS upon successful T/APC conjugate formation, we hypothesized that accumulation of CD38 at the T/APC contact might occur. This contact area is also highly enriched in lipid rafts. These are used as platforms for the assembly of the TCR signaling complex and contain a number of constitutive or recruited proteins. [12][13][14] CD38 establishes associations with distinct surface molecules, which vary according to cell lineage. In monocytes CD38 shares with HLA class II and CD9 a common activation pathway, 15 and the association is implemented before monocytes interact with T lymphocytes. 16 Dynamic changes in these molecular associations, such as recruitment of other surface and/or signaling molecules, may occur during the formation and establishment of the relevant synapses. Thus, binding of ICAMs to LFA-1 expressed by mature dendritic cells (DCs) induces HLA class-II clustering into the IS. 17 Tetraspanins as CD81 are also dynamically redistributed during synapse formation, 18 with CD38, CD83, CD11b, and CCR7 translocated to a pole of mature DCs upon mAb crosslinking. 19 Therefore, it is also conceivable that CD38 in the APCs may translocate at the IS upon antigen presentation.This study shows that CD38 is recruited to the T/APC interface, and that T cells and APCs to a lesser extent contribute to the clustering of this molecule to IS. The results also indicate that CD38 expression in T cells may contribute to modulate specific antigen-mediated early and late T-cell responses during IS formation. The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. MethodsCells, [20][21][22][23][24] antibodies, and reagents used are listed in Document S1 (available on the Blood website; see the Supplemental Materials link at the top of the online article). CD38-GFP construct and transient ...