Unidirectional signaling triggered through 2B4 (CD244), not CD48, in murine NK cells

Abstract

Engagement of 2B4 (CD244) with CD48 results in activation, costimulation, or inhibition of NK cell activities, depending on the cell types and the stage of differentiation. In vivo, 2B4+ NK cells can interact with CD48+ NK cells and also with surrounding CD48+ hematopoietic cells. Similarly, CD48+ NK cells may be triggered by adjacent 2B4+ NK cells or other hematopoietic cells expressing 2B4, e.g., monocytes, basophils, γδ T cells, etc. As CD48 was also shown to function as an activating receptor, 2B4/CD48 binding in the settings of NK-to-NK or NK-to-non-NK cell interactions may generate bidirectional signals. To address this question, we examined the consequence of CD48 or 2B4 ligation using two experimental settings: one with target (syngeneic EL4 and allogeneic P815) cells, ectopically expressing surface 2B4 or CD48, and the other with direct cross-linking with plate-bound mAb. Here, we report that ligation of CD48 with 2B4+ EL4 or 2B4+ P815 targets, in the absence of other receptor engagement, did not alter NK cell cytotoxicity or proliferation significantly. Similarly, cross-linking of NK cells with plate-bound anti-CD48 mAb in the absence or presence of a suboptimal dose of IL-2 did not modulate NK proliferation, cytotoxicity, or cytokine production. Nonetheless, 2B4 cross-linking promoted NK cell proliferation and effector functions consistently in both settings. Therefore, our results demonstrate unequivocally that CD48 on surrounding NK or non-NK cells serves primarily as a ligand to stimulate 2B4 on the adjacent NK cells in mice.

Enhancement of Antigen-Specific Immunoglobulin G Responses by Anti-CD48

“…These results are also consistent with recent findings that the involvement of CD244 in T-cell-mediated stimulation of B-cell responses does not require NK cells [28]. Thus, despite findings from in vitro experiments that anti-CD244 can directly activate NK cells, in vivo, the function of these cells may be dampened by the presence of CD48-expressing cells [29]. …”

Leishmania-Infected Macrophages Are Targets of NK Cell-Derived Cytokines but Not of NK Cell Cytotoxicity

“…1 and data not shown). Importantly, infection with Leishmania did not increase the susceptibility of myeloid cells to NK cell-mediated ϩ PE-M, and CD11b ϩ CD11c ϩ BM-DCs for the surface expression of (i) MHC class I antigens (the ligands for the inhibitory members of the Ly49 NK cell receptor family) and Qa-1 b (a nonclassical MHC-like molecule that primarily functions as a high-affinity ligand of the inhibitory NK cell receptor NKG2A [13]); (ii) CD48, which interacts with the 2B4 receptor on NK cells and transmits inhibitory or activating signals, depending on the degree of receptor expression and cross-linking (11,27); and (iii) Rae-1␣ and MULT-1, which are ligands of the activating NK cell receptor NKG2D (31). In general, infection of the three different myeloid cell populations with L. infantum promastigotes did not alter the expression of these ligands.…”

The Peripheral NK Cell Repertoire after Kidney Transplantation is Modulated by Different Immunosuppressive Drugs

“…In addition, expression of NKG2D, CD48, and DNAM-1 as well as clustering of adhesion molecules such as CD2, CD58, and CD49d was found to be reduced (Kim et al, 2010). Since no alteration of DNAM-1 expression on NK cells could be observed in our kidney transplanted patient cohort (data not shown), it can be assumed that the disease context has substantial influence on the sensitivity of NK cell receptors toward immunosuppressive drugs.…”

“…In contrast, the involvement of the mTOR pathway is currently intensively for regulatory T cells (Treg) in comparison to effector T cells (Kim et al, 2010). While both pathways were studied primarily in T cells as primary target cells of CNI, only limited information was available regarding the effect of CNI vs. a combination with mTORi on the composition of NK cell subsets in patients after kidney transplantation.…”