NK Cells: New Partners in Antibody-Triggered Chronic Rejection
Version of Record online: 9 NOV 2011
© 2011 The American Society of Transplantation and the American Society of Transplant Surgeons
American Journal of Transplantation
Volume 12, Issue 2, pages 275–276, February 2012
How to Cite
Li, X. C. and Baldwin, III, W. M. (2012), NK Cells: New Partners in Antibody-Triggered Chronic Rejection. American Journal of Transplantation, 12: 275–276. doi: 10.1111/j.1600-6143.2011.03839.x
- Issue online: 27 JAN 2012
- Version of Record online: 9 NOV 2011
- Received 12 September 2011, revised 27 September 2011 and accepted for publication 28 September 2011
The innate NK cells are frequently found in rejecting allografts, but the role of NK cells in solid organ transplantation has defied our understanding until recently. Studies from several laboratories now suggest that NK cells are intimately involved in regulating whether a transplant is rejected or accepted. In addition, recent findings that NK cells can acquire additional features (besides killing and cytokine production) that are traditionally ascribed to adaptive T cells (e.g. memory phenotype), suggest that NK cells may have a much broader role in the overall immune responses (1).
In this issue of the American Journal of Transplantation, Hirohashi et al. discovered an unexpected role for NK cells in chronic allograft rejection induced by donor-specific antibodies (DSA; Ref. 2). The model employed by the authors is a straightforward one, in which DSA were infused into immunodeficient Rag–/– mice that were grafted with heart allografts to which the DSA were directed. In this model, transplant vasculopathy (i.e. concentric neointima formation), a hallmark of chronic allograft rejection, was consistently induced within a time frame of 4 weeks. In a series of elegant experiments, the authors came up with three major observations. First, NK cells are absolutely needed for the development of full-fledged vascular lesions in the grafts, as neither NK depleted mice nor recipient mice genetically deficient for NK cells (Rag–/–γc–/– mice) developed transplant vasculopathy. Second, a role for the Fc portion of DSA is indicated in this model. This is because infusion of the F(ab’)2 fragment of DSA, even at doses much higher that the intact DSA, failed to induce vasculopathy in the graft. Third, complement is dispensable; the authors provided solid evidence that transplant vasculopathy can be induced with noncomplement-fixing DSA or in C3-deficient Rag–/– mice in which complement activation is inhibited. Together, these findings illuminate a novel pathway of chronic allograft rejection in which DSA must partner with NK cells (not with complement) to trigger transplant vasculopathy. This revelation is important; as it may open new opportunities to improve transplant survival by targeting the NK/DSA pathway.
Although exciting, this study raises unresolved questions that require further clarification. The role of NK cells in DSA-induced chronic rejection is convincing, but how NK cells function to promote this vasculopathy is less clear. Individual NK cells express both activating receptors and inhibitory receptors, and the ubiquitously expressed self-MHC class I molecules serve as the principal ligands for the NK inhibitory receptors. Thus, it is the self-MHC class I molecules that enforce NK tolerance (3), and because of that, NK cells can respond to allotransplants that lack host type MHC class I, a process often called “missing self” recognition. This type of recognition will unleash the killing activities of NK cells against the grafts (4). However, this type of NK alloreactivity seems not involved in the vascular lesions, because transplant vasculopathy remains a prominent feature in F1 recipients, where the NK alloreactivity is absent. The requirement of Fc suggests that NK cells must interact with DSA bound to vascular endothelial cells to induce vascular damage. NK cells express Fc receptors, and endothelial activation is involved in vascular lesions. In fact, Erk activation in vascular endothelial cells in the heart transplants seems compatible with this notion. However, other cells, especially macrophages, have a greater array of Fc receptors for antibodies than NK cells; and macrophages express multiple high affinity Fc receptors, whereas NK cells only express a low affinity Fc receptor CD16. Intriguingly, macrophages are not sufficient to induce the transplant vasculopathy in this model. Alternatively, bound DSA may trigger NK activation via engagement of the Fc receptor and indirectly damage the vascular endothelium by activated NK cells (Figure 1). In this scenario, DSA may act as a major activating signal for NK cells. However, the attributes of NK cells activated in this fashion are less well understood.
Another issue that deserves some attention is the exact role of graft vascular endothelial cells in vascular lesions, and whether they are victims of NK cells or active contributors to transplant vasculopathy. Clearly, DSA can trigger Erk activation in vascular endothelial cells in the graft, but this event must be paired with NK cells to produce transplant vasculopathy, as shown by Hirohashi et al. (2). Although not emphasized by the authors, the NK cells and vascular lesions are confined to coronary arteries near the ostia in the graft. This site shares common features with human coronary arteries; namely, adipose tissue surrounds arteries that traverse the epicardium. Adipose tissue in general, and perivascular adipose tissue in particular, has been found to be a very active source of cytokines and growth factors that support the growth and function of various leukocytes, including macrophages and NK cells (5). Whether other sites (e.g. the epicardial segments of mouse coronary arteries) might capture similar features in this model should be explored.
Finally, in both clinical observations and animal models, the effects of complement are most evident in small vessels, particularly capillaries. In heart transplants, C4d and C3d are considered diagnostically significant only in the capillaries. It is well recognized that chronic allograft rejection can also involve large and/or small vessels in the grafts. Interestingly, Lu et al. recently reported that vasculopathy in heart transplant patients was widespread in epicardial arteries, but involved only a minority of intramyocardial arteries and was rarely diagnosed in endomyocardial arteries (6). So, the contribution of complement to chronic rejection still needs to be better defined. It is important to know the in vivo circumstances where complement activation will or will not trigger vascular lesions in transplant models.
Despite these issues, the studies by Hirohashi et al. uncover a previously unknown mechanism of chronic rejection that requires NK cells independently of complements. This finding sharply focuses the limelight on innate immune cells in transplant vasculopathy.
The authors of this manuscript have no conflicts of interests to disclose as described by the American Journal of Transplantation.