Molecular Basis of the Dual Functions of 2B4 (CD244)

Chlewicki, Lukasz K.; Velikovsky, Carlos A.; Balakrishnan, Vamsi; Mariuzza, Roy A.; Kumar, Vinay

doi:10.4049/jimmunol.180.12.8159

Cited by 123 publications

(136 citation statements)

References 60 publications

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“…Thus, lack of SAP binding to 2B4, observed in x-linked lymphoproliferative disease patients, likely converts activating 2B4 into inhibitory via associated tyrosine phosphatases. Consistent with this hypothesis, SAP expression was shown to be upregulated upon activation (41), and relative paucity of SAP failed to deliver signals to 3BP2 and subsequent PLC-␥ and ERK activation (42). Unlike 2B4, the role of CD2 in control of NK effector functions was found to be specific to human, not murine, NK cells.…”

Section: Discussionsupporting

confidence: 61%

Homotypic Cell to Cell Cross-talk Among Human Natural Killer Cells Reveals Differential and Overlapping Roles of 2B4 and CD2

Kim

et al. 2010

Journal of Biological Chemistry

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Human natural killer (NK) cells express an abundant level of 2B4 and CD2 on their surface. Their counter-receptors, CD48 and CD58, are also expressed on the NK cell surface, raising a question about the functional consequences of potential 2B4/ CD48 and CD2/CD58 interactions. Using blocking antibodies specific to each receptor, we demonstrated that both 2B4/ CD48 and CD2/CD58 interactions were essential for the development of NK effector functions: cytotoxicity and cytokine secretion. However, only 2B4/CD48, but not CD2/CD58, interactions were shown to be critical for the optimal NK cell proliferation in response to interleukin (IL)-2. IL-2-activated NK cells cultured in the absence of 2B4/CD48 or CD2/CD58 interactions were severely impaired for their ability to induce intracellular calcium mobilization and subsequent ERK activation upon tumor target exposure, suggesting that the early signaling pathway of NK receptors leading to impaired cytolysis and interferon (IFN)-␥ secretion was inhibited. Nevertheless, these defects did not fully account for the reduced proliferation of NK cells in the absence of 2B4/CD48 interactions, because anti-CD2 or anti-CD58 monoclonal antibody (mAb)-treated NK cells, showing defective signaling and effector functions, displayed normal proliferation upon IL-2 stimulation. These results propose the signaling divergence between pathways leading to cell proliferation and cytotoxicity/cytokine release, which can be differentially regulated by 2B4 and CD2 during IL-2-driven NK cell activation. Collectively, these results reveal the importance of homotypic NK-to-NK cell cross-talk through 2B4/CD48 and CD2/CD58 pairs and further present their differential and overlapping roles in human NK cells.2B4 (CD244) belongs to the CD2 family along with CD48, CD2, CD58 (LFA-3), CD84 (GR6), Ly9 (CD229), SLAM, NTB-A, and CRACC. Receptors within this family have been implicated in homophilic and heterophilic self-interactions (1). Among them, CD84, Ly9, SLAM, NTB-A, and CRACC are all self-ligands and receptors, and up-regulated in NK 6 cells as well as T cells, B cells, dendritic cells, and macrophages (2). In both mouse and human, CD48 appears to be a high affinity ligand for 2B4, as well as a weak ligand for CD2 (3). Although mouse NK cells in the resting state express both 2B4 and CD2, only 2B4, but not CD2, was found to play a major role in the activation and expansion of NK cells (4, 5). The preferential role of 2B4 over CD2 in murine NK cells appears to be due to its high affinity interaction with CD48 because 2B4 binds to CD48 with 5-10-fold higher affinity than CD2 (6). Furthermore, murine 2B4 was shown to function as a costimulatory receptor in response to cytokine (IL-2 or IFN-␣) stimulation, via triggering cell to cell cross-talk through binding to CD48 expressed on neighboring NK cells (7). These homotypic interactions via 2B4/CD48 were found to be necessary for optimal expansion, lytic potential, and cytokine secretion in murine NK cells (7). Additionally, murine 2B4 could also function as...

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Section: Discussionsupporting

confidence: 61%

Homotypic Cell to Cell Cross-talk Among Human Natural Killer Cells Reveals Differential and Overlapping Roles of 2B4 and CD2

Kim

et al. 2010

Journal of Biological Chemistry

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“…We specifically examined the correlation between MSC licensing and T cell cytokine suppression with MSC expression of galectin-9 (34), TRAIL (35), HLAG (36), TNFR (37), SLAM2 (38), HLAC (39), OX40L (40), CD200R (41), FASL (42), and B7H1/B7DC (26). Among these, we identified and validated B7H1 and B7DC as the sole inhibitory contact factors deployed by IFN-g licensing (26).…”

Section: Discussionmentioning

confidence: 99%

IDO-Independent Suppression of T Cell Effector Function by IFN-γ–Licensed Human Mesenchymal Stromal Cells

Chinnadurai

Copland

Patel

et al. 2014

The Journal of Immunology

231

214

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Human bone marrow–derived mesenchymal stromal cells (MSCs) inhibit proliferation of activated T cells, and IFN-γ plays an important role in this process. This IFN-γ–licensed veto property is IDO-dependent. To further decipher the mechanistic underpinnings of MSC veto function on T cells, we investigated the effect of MSCs and IFN-γ–licensed MSCs on T cell effector function as assayed by cytokine secretion of T cells. Although MSCs and IFN-γ–licensed MSCs inhibit T cell proliferation, only IFN-γ–licensed MSCs significantly inhibit Th1 cytokine (IFN-γ, TNF-α, and IL-2) production by T cells. Additionally, IFN-γ–licensed MSCs inhibit T cell degranulation as well as single, double, and triple cytokine–producing T cells. Although IFN-γ–licensed MSCs upregulate their IDO activity, we found that MSC IDO catalytic function is dispensable with regard to MSC-driven inhibition of T cell effector function. Novel flow cytometry based functional screening of MSC-expressed, IFN-γ–licensed inhibitory molecules identified B7H1 and B7DC/PD1 pathways as essential effectors in blocking T cell function. Small interfering RNA–mediated blocking of B7H1 and B7DC reverses the inhibitory potential of IFN-γ–licensed MSCs on T cell effector function. Mechanistic analysis revealed that clustering of MHC and coinhibitory molecules are indispensable for the inhibitory effect of IFN-γ MSCs. Although exogenous IL-2 reverses B7H1-Ig–mediated inhibition of T cell proliferation, it does not affect the veto function of IFN-γ MSCs on both T cell proliferation and effector function. Our results reveal a new immunosuppressive property of IFN-γ–licensed MSCs that inhibits T cell effector function independent of IDO but through the ligands for PD1.

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“…Although, recent reports suggest that 2B4 in humans and mice may have dual function of a single receptor-ligand pair that is regulated by cell surface density, degree of cross-linking, and the abundance or limitation of adaptor molecules [25]. It seems likely that human and mouse 2B4 engages CD48 with similar docking topologies [26].…”

Section: Introductionmentioning

confidence: 99%

Functional role of human NK cell receptor 2B4 (CD244) isoforms

et al. 2009

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TX, USA2B4 (CD244), a member of the signaling lymphocyte-activation molecule (SLAM/CD150), is expressed on all NK cells, a subpopulation of T cells, monocytes and basophils. Human NK cells express two isoforms of 2B4, h2B4-A and h2B4-B that differ in a small portion of the extracellular domain. In the present investigation, we have studied the functions of h2B4-A and h2B4-B. Our study demonstrated that these two isoforms differ in their binding affinity for CD48, which results in differential cytotoxic activity as well as intracellular calcium release by NK cells upon target cell recognition. Analysis of the predicted 3-D structure of the two isoforms showed conformational differences that could account for their differences in binding affinity to CD48. h2B4-A was able to mediate natural cytotoxicity against CD48-expressing K562 target cells and induce intracellular calcium release, whereas h2B4-B showed no effects. NK-92MI, U937, THP-1, KU812, primary monocytes, basophils and NK cells showed expression of both h2B4-A and h2B4-B whereas YT and IL-2-activated NK cells did not show any h2B4-B expression. Stimulation of NK cells through 2B4 resulted in decreased mRNA levels of both h2B4-A and h2B4-B indicating that down-regulation of 2B4 isoforms may be an important factor in controlling NK cell activation during immune responses.Key words: Cell activation . Cell surface molecules . NK cells Introduction NK cells are a fundamental component of the innate immune system, capable of recognizing and destroying tumor cells as well as cells that have been infected by viruses or bacteria [1]. In addition to their role in innate immune responses, interactions between NK cells and dendritic cells regulate the adaptive immune response to pathogens [2]. NK cell functions are regulated by a dynamic interplay between activating and inhibitory signals transmitted by distinct classes of receptors found on their surface [3,4]. The balance between positivesignaling receptors and negative-signaling receptors ultimately determines the outcome of NK cell-target cell encounters [5,6].2B4 (CD244), belongs to the signaling lymphocyte-activation molecule (SLAM) family of receptors, which includes SLAM (CD150), CD84, NTB-A (Ly-108), lymphocyte antigen 9 (Ly9; CD229), and CD2-subset 1 (CS1) (also termed CRACC or CD319) [7][8][9][10]. 2B4 is expressed by all NK cells, as well as a subset of memory CD8 1 abT cells, gdT cells, basophils, monocytes and eosinophils [11][12][13][14][15]. 2B4 binds to the glycophosphoinositol anchored protein, CD48, expressed on all hematopoietic cells, with a similar affinity in mouse and human [16,17]. Engagement of 2B4 via interaction with specific antibodies or CD48 induces cytokine secretion (IFN-g) and enhances non-MHC-restricted 1632killing by NK cells [12,16,18]. 2B4 can also function as a ligand on target cells and stimulate NK cells through the engagement of CD48 [19]. 2B4 was initially identified as an activating receptor in non-MHC-restricted killing of NK and T cells [12,20]. Some studies with human ...

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Molecular Basis of the Dual Functions of 2B4 (CD244)

Cited by 123 publications

References 60 publications

Homotypic Cell to Cell Cross-talk Among Human Natural Killer Cells Reveals Differential and Overlapping Roles of 2B4 and CD2

Homotypic Cell to Cell Cross-talk Among Human Natural Killer Cells Reveals Differential and Overlapping Roles of 2B4 and CD2

IDO-Independent Suppression of T Cell Effector Function by IFN-γ–Licensed Human Mesenchymal Stromal Cells

Functional role of human NK cell receptor 2B4 (CD244) isoforms

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