To achieve donor-specific immune tolerance to allogeneic organ transplants, it is imperative to understand the cell types involved in acute allograft rejection. In wild-type mice, CD4 + T cells are necessary and sufficient for acute rejection of cardiac allografts. However, when T-cell responses are suboptimal, such as in mice treated with costimulation-targeting agents or in CD28-deficient mice, and perhaps in transplanted patients taking immunosuppressive drugs, the participation of other lymphocytes such as CD8 + T cells and NK1.1 + cells becomes apparent. We found that host NK but not NKT cells were required for cardiac rejection. Ly49G2 + NK cells suppressed rejection, whereas a subset of NK cells lacking inhibitory Ly49 receptors for donor MHC class I molecules was sufficient to promote rejection. Notably, rejection was independent of the activating receptors Ly49D and NKG2D. Finally, our experiments supported a mechanism by which NK cells promote expansion and effector function of alloreactive T cells. Thus, therapies aimed at specific subsets of NK cells may facilitate transplantation tolerance in settings of impaired T-cell function.

IntroductionThe CD2 family of receptors is part of the immunoglobulin (Ig) superfamily, which includes CD2, 2B4 (CD244), CD48, CD58, SLAM (CD150), CS1, CD84, Ly-9, NTBA (SF2000, Ly108), SF2001 (CD2-F10), and BLAME (B-lymphocyte activator macrophage expressed). 1,2 The CD2 family members are expressed predominantly on hematopoietic cells and have been shown to interact with other molecules of the same subfamily or with themselves. SLAM, CD84, CS1, and NTBA are found to be self-ligands and to mediate homophilic interaction. For example, SLAM expressed on activated T cells binds to SLAM on B cells and promotes their activation. 3-5 CD84 on T cells binds to CD84-Ig fusion protein and enhances IFN-␥ secretion on anti-CD3 mAbmediated T-cell crosslinking. 6 CS1 and NTBA on natural killer (NK) cells augment NK cytotoxicity by homophilic interactions. 7,8 Unlike these receptors, there is no evidence for 2B4-or CD2-mediated homophilic interaction. Instead, CD48, expressed widely on hematopoietic cells including T and NK cells, has been identified as a ligand for 2B4 and CD2. Although both 2B4 and CD2 bind to CD48, the affinity of 2B4 to CD48 is 5-to 10-fold higher than that of CD2. 9 Thus, 2B4/CD48 interaction is likely to dominate over CD2/CD48 interaction in cells coexpressing 2B4, CD2, and CD48, such as NK cells. However, in naive T cells, 2B4 is not expressed; thus, the primary receptor for CD48 in such cells appears to be CD2. 10 2B4 was initially identified as an activating receptor. 11-15 However, more recent studies with human NK cells suggest that 2B4 may not itself be a triggering receptor but instead function as a coreceptor for other NK-associated activating receptors such as NKp46. 16 Similarly, ectopic expression of 2B4 in activated mouse CD8 T cells resulted in T-cell receptor (TCR)-dependent augmentation of cytolysis against antigenic targets. 17 These data suggest that the primary role of 2B4 in both T cells and NK cells may be to regulate other receptor/ligand interactions. There is, however, evidence that 2B4 can act as an inhibitory receptor in both humans 18 and mice. 19,20 Our recent studies show that in murine NK cells 2B4 functions as an inhibitory receptor rather than a costimulatory receptor when engaged by CD48-expressing tumor targets. 19 The mechanism by which 2B4 mediates such opposing functions in mice still remains to be determined. Nevertheless, these data strongly 21 shows that 2B4/CD48 interaction among NK cells and NK-T cells exists and regulates cell proliferation. We confirm that 2B4 interaction with CD48 among NK cells is necessary for optimal expansion and reveal that such an interaction is critical for optimal cytolytic activation of NK cells, IFN-␥ secretion, and elimination of tumor cells in vivo. Our data, therefore, reveal a previously unknown mechanism of augmented NK effector functions by homotypic 2B4/CD48 interaction. Materials and methods MiceC57BL/6 mice between 6 and 12 weeks of age were purchased from Frederick Cancer Research and Developmental Center (National Cancer...

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