What is the Missing Self Hypothesis?
MHC class I molecules (Human MHC is called HLA) are typically expressed on the cell surface by all body cells save some specific cell types such as sperm and eggs. In the 1980s, the Swedish immunologistnoticed reduced (down-regulation) cell-surface MHC class I expression was fairly common following viral infections, cancerous transformation and other types of cellular stress, and that precisely such lack of surface MHC class I seemed to make such cells a target for cytotoxic killing by NK cells ( ). Karre postulated that some then as-yet unknown NK receptors were scanning cell surfaces for presence or absence of MHC class I molecules, getting activated and killing those that lacked cell-surface MHC class I, i.e., Missing Self ( , 2). This is a very different process from how cytotoxic CD8 T cells engage antigen-derived epitopes presented within MHC class I molecules.
Circa 2017, Missing Self is much more complicated, outcome of as-yet incompletely understood interactions of a dizzying array of NK cell activating and inhibitory receptors called KIRs.
Thirty years on, the Missing Self idea is clearly not so simple. NK cells themselves seem far more complex than just innate immune cells with invariable germline-encoded receptors. Instead, parallel to and complementing T and B cells, NK cells seem to have evolved a highly complex and more pertinently, highly specific process for recognizing their target cells (), a process strikingly different from the one used by T cells, which is of somatically rearranged cell-surface receptors binding MHC-bound peptides on presenting cells.
Rather, NK cells express a wide array of cell surface activating and inhibitory receptors, the KIRs (), and outcome depends on the balance of what they bind, namely, MHC class I as well as as-yet unknown ligands expressed on target cells (see below from ).
NK cells appear to get activated when multiple activating KIRs are engaged, which overrides inhibitory KIR binding. There is as yet no consensus of how KIRs help shape NK cell ‘education’ during their development in the bone marrow, especially how they learn self-tolerance, with a variety of models, Arming, Disarming, Confining, (5,) emphasizing different aspects of the process while the Rheostat model favored by the Swedish group tries to encompass them (see below from ).
More recent studies complicate matters further by suggesting NK KIRs are sensitive to peptides presented by the HLA class I molecule (). Also worth noting that most of these models are based on data generated using circulating (blood) NK cells and who knows whether or how relevant such models are to tissue-resident NK cells such as uterine NK cells, whose proper functioning is known to be critical for healthy pregnancies through NK cell KIR engagement by placental trophoblast HLA-C ( ), and where proper uNK cell functioning includes extensive uterine tissue remodeling through cytokine secretion to help it quickly adapt to increased vascular supply for the growing fetus ( ).
Could mismatch between NK Cell KIRs and tissue KIR ligands Influence transplant rejection?
Since most transplants are allogeneic, between genetically non-identical individuals (), HLA matching is done to reduce scope of T cell-mediated rejection. Do transplants need NK cell KIR and tissue KIR ligand matching as well? Available data is somewhat confusing as would be expected with triggers that activate or inhibit NK cells remaining not fully defined.
Nevertheless, since the early 2000s, a steady drip of scientific articles suggest KIR-KIRL (KIR ligands including HLA) matching could improve long-term kidney transplant survival while more recent studies suggest such matching may matter for other transplants such as liver as well. OTOH, in what surely sounds surprising, KIR-HLA mismatching might also improve graft tolerance by killing donor antigen-presenting cells, which would reduce direct antigen presentation by graft.
Thus, even with HLA compatible transplants, recipient NK cells expressing an inhibitory receptor could be activated by allograft cells that lack the HLA class I ligands relevant for that particular inhibitory receptor (11).
Human kidney transplants in particular suggest NK cell mismatch in terms of NK cell inhibitory KIR receptors and missing HLA class I can adversely affect long-term renal allograft survival.
While at least one study () that retrospectively analyzed KIR ligand mismatches in 608 cadaveric kidney grafts didn’t find significant differences in 10-year graft survival rates, many other studies ( , , , , , ) support the idea that KIR matching in addition to HLA matching would improve long-term renal graft survival.
One study found KIR-KIRL matching to affect liver rejection rates with higher acute rejection for mismatches ().
Finally, it’s also worth remembering that NK cells could also be activated to damage allografts through ADCC (), a process dependent on their antibody-binding , not on KIRs ( ).
1. Kärre, Klas, et al. “Selective rejection of H–2-deficient lymphoma variants suggests alternative immune defence strategy.” Nature 319.6055 (1986): 675-678.
2. Ljunggren, Hans-Gustaf, and Klas Kärre. “In search of the ‘missing self’: MHC molecules and NK cell recognition.” Immunology today 11 (1990): 237-244.
3. Yawata, Makoto, et al. “MHC class I–specific inhibitory receptors and their ligands structure diverse human NK-cell repertoires toward a balance of missing self-response.” Blood 112.6 (2008): 2369-2380.
4. Rajalingam, Raja. “The impact of HLA class I-specific killer cell immunoglobulin-like receptors on antibody-dependent natural killer cell-mediated cytotoxicity and organ allograft rejection.” Frontiers in immunology 7 (2016).
5. Höglund, Petter, and Petter Brodin. “Current perspectives of natural killer cell education by MHC class I molecules.” Nature reviews. Immunology 10.10 (2010): 724.
6. He, Yuke, and Zhigang Tian. “NK cell education via nonclassical MHC and non-MHC ligands.” Cellular and Molecular Immunology 14.4 (2017): 321.
7. Kadri, Nadir, et al. “Dynamic regulation of NK cell responsiveness.” Natural Killer Cells. Springer International Publishing, 2015. 95-114.
8. Carrillo-Bustamante, Paola, Rob J. de Boer, and Can Keşmir. “Specificity of inhibitory KIRs enables NK cells to detect changes in an altered peptide environment.” Immunogenetics (2017): 1-11.
9. Hiby, Susan E., et al. “Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success.” Journal of Experimental Medicine 200.8 (2004): 957-965.
10. Rätsep, Matthew T., et al. “Uterine natural killer cells: supervisors of vasculature construction in early decidua basalis.” Reproduction 149.2 (2015): R91-R102.
11. Rajalingam, Raja. “Variable interactions of recipient killer cell immunoglobulin-like receptors with self and allogenic human leukocyte antigen class I ligands may influence the outcome of solid organ transplants.” Current opinion in organ transplantation 13.4 (2008): 430-437.
12. Tran, T. H., et al. “No Impact of KIR‐Ligand Mismatch on Allograft Outcome in HLA‐Compatible Kidney Transplantation.” American Journal of Transplantation 13.4 (2013): 1063-1068.
13. van Bergen, Jeroen, et al. “KIR‐ligand mismatches are associated with reduced long‐term graft survival in HLA‐compatible kidney transplantation.” American Journal of Transplantation 11.9 (2011): 1959-1964.;
14. Rajalingam, R., and H. M. Gebel. “KIR‐HLA Mismatching in Human Renal Allograft Transplantation: Emergence of a New Concept.” American Journal of Transplantation 11.9 (2011): 1771-1772.
15. Kunert, Kristina, et al. “KIR/HLA ligand incompatibility in kidney transplantation.” Transplantation 84.11 (2007): 1527-1533.
16. Vampa, Maria Luisa, et al. “Natural killer-cell activity after human renal transplantation in relation to killer immunoglobulin-like receptors and human leukocyte antigen mismatch1.” Transplantation 76.8 (2003): 1220-1228.
17. Nowak, Izabela, et al. “Killer immunoglobulin-like receptor (KIR) and HLA genotypes affect the outcome of allogeneic kidney transplantation.” PloS one 7.9 (2012): e44718.
18. Littera, Roberto, et al. “KIR and their HLA Class I ligands: Two more pieces towards completing the puzzle of chronic rejection and graft loss in kidney transplantation.” PloS one 12.7 (2017): e0180831.
19. Legaz, Isabel, et al. “KIR gene mismatching and KIR/C ligands in liver transplantation: consequences for short-term liver allograft injury.” Transplantation 95.8 (2013): 1037-1044.