Review2B4 co-stimulation: NK cells and their control of adaptive immune responses
Introduction
As part of the innate immune system, NK cells play an important role in the early defense against certain viruses, microbial infections and cancer (Bancroft, 1993, Tay et al., 1998, Biron and Brossay, 2001, Cerwenka and Lanier, 2001). NK cells were originally identified for their ability to kill tumor cells in vitro without the need for prior activation. NK cells are also potent producers of several cytokines including IFNγ, TNFα, and GM-CSF (Perussia, 1991). These cytokines provide important immunoregulatory properties by which NK cells can affect anti-microbial and anti-tumor responses as well as influence the outcome of autoimmune and hypersensitivity reactions (Shi et al., 2001). NK cells have also been reported to influence CTL and B cell responses (Perussia, 1991, Bancroft, 1993, Gray and Horwitz, 1995, Wilder et al., 1996, Kos, 1998).
A number of receptor–ligand pairs have been shown to modulate lymphocyte responses. Among these are members of the CD2-subset of the immunoglobulin family of receptors, including CD2, CD48, CD58, CD84, SLAM, 2B4, and Ly-9 (Tangye et al., 2000). One of the more studied receptor–ligand pairs is CD2 and CD48, which lowers quantitative thresholds and fine-tunes T cell activation both in vitro and in vivo (Blazar et al., 1998, Sido et al., 1998, Bachmann et al., 1999, Punch et al., 1999). 2B4 (CD244) is a cell surface glycoprotein that is expressed on all NK cells, skin γδ+ T cells, and a subset of CD8+ T cells with memory/effector phenotype (Schuhmachers et al., 1995a, Nakajima and Colonna, 2000, Kambayashi et al., 2001). Like CD2, 2B4 binds to CD48, but with six- to nine-fold greater affinity (Brown et al., 1998). Engagement of 2B4 on NK cells with specific antibodies leads to secretion of IFNγ and increased cytotoxicity (Nakajima and Colonna, 2000). Interestingly, a recent study performed with 2B4−/− mice have demonstrated that 2B4 may act chiefly as an inhibitory receptor (Lee et al., 2004).
Although crosslinking of 2B4 on NK cells stimulates lytic activity, IFNγ secretion, and granule exocytosis (Valiante and Trinchieri, 1993, Boles et al., 1999, Nakajima et al., 1999), only a few studies have addressed the function of 2B4 when expressed on other cell types (Schuhmachers et al., 1995b, Kambayashi et al., 2001, Lee et al., 2003). Crosslinking of 2B4 on a subset of γδ+ T cells leads to stimulation of IFNγ and IL-2 production as well as enhanced proliferation (Schuhmachers et al., 1995b). Furthermore, two studies have shown that 2B4–CD48 interactions between T cells can augment the T cell function (Kambayashi et al., 2001, Lee et al., 2003). While we have observed 2B4 expression on at least a subset of dendritic cells, to date we do not know what the function of 2B4 is on these cells (our unpublished observations).
Section snippets
NK cell-T cell interaction
The cytokine milieu formed by NK cells during an infection plays a central role in influencing the outcome of T cell-mediated immune responses. However, it has not been addressed whether direct cellular interactions between NK cells and T cells could influence T cell responses. Since NK cells constitutively express 2B4, we asked whether NK cells could also co-stimulate T cells in vitro. Upon CD3-crosslinking, T cell proliferation was enhanced in the presence of NK cells. The enhanced
How does 2B4 induce responses?
Apart from being an inhibitory or activating receptor on NK cells (Schatzle et al., 1999, Stepp et al., 1999, Lee et al., 2004), 2B4 now appears to act as a ligand for CD48 expressed on other cells (Kambayashi et al., 2001, Assarsson et al., 2004). However, the signals through CD48 upon 2B4 ligation have not yet been dissected. Antibody crosslinking of CD48 has previously been shown to increase the proliferative response of anti-CD3-stimulated CD8+ T cells (Kato et al., 1992). These findings
Does 2B4 play a role in T cell co-stimulation in vivo?
While the co-stimulation of T cells by 2B4 has been examined in vitro, it remains to be seen whether it has any affect on T cells in vivo. Anti-CD48 antibodies suppress T cell responses and reduce NK cell responses in vivo (Chavin et al., 1994). In addition, T cells from CD48−/− mice have a severe reduction in proliferation and IL-2 production in response to lectins, anti-CD3 antibodies, and alloantigens (Gonzalez-Cabrero et al., 1999). CD2 was initially identified as a receptor for CD48 and
The role of NK cells in T cell responses in vivo
The role of NK cells in determining the fate of adaptive immune responses is intriguing and may have implications in the development of anti-tumor treatments as well as the prevention of autoimmunity. NK cells can affect T cell responses by eliminating dendritic cells in vivo (Hayakawa et al., 2004), and they suppress the induction of some autoimmune diseases (Flodstrom et al., 2002). The localization of NK cells in lymphoid organs has been analyzed in detail (Brown et al., 2001). The numbers
Acknowledgements
We thank all our collaborators who have helped in this work. This work was supported by the Swedish Foundation for Strategic Research, the Karolinska Institutet, the Swedish Research Council, the Swedish Cancer Society, the Tobias Foundation, the Åke Wiberg Foundation, the Alex and Eva Wallström Foundation, the Lars Hiertas Foundation, the Swedish Foundation for International Cooperation in Research and Higher Education, and the Swedish Society for Medical Research.
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