A New Way for Natural Killers to Find Their “Missing-Self”

To battle infections and cancers, immune cells face the almost existential question of what is self and what is nonself. Immune cells must constantly decide whether cells are healthy parts of the body or whether they are infected with foreign invaders such as viruses or are transformed cells such as cancer cells. One type of immune cell that has evolved to address this issue is natural killer (NK) cells, which detect “missing-self” by expressing an array of activating and inhibitory receptors. Self-markers such as certain human lymphocyte antigen proteins in humans and major histocompatibility complex class I (MHC I) molecules in mouse help train these skilled assassins. These receptors professionally license the NK cell to respond robustly while at the same time inhibiting NK cells from attacking self. Now, Andrews and colleagues discover that another training marker—H2-M3, a “nonclassical” MHC I molecule—regulates the NK response as well. To do this, the authors built on the observation that NK cells from an H2-M3–deficient mouse appeared incompletely licensed or less capable of killing. Ly49A, a well-characterized inhibitory receptor on NK cells, is known to bind MHC I molecules with likely homology to H2-M3. The authors established that peptide-loaded H2-M3 proteins could stain cells that expressed Ly49A but not other Ly49 subtypes. In two mouse models of cancer, the authors observed that mice deficient in H2-M3 had greater numbers of melanoma metastases to lung and higher rates of fibrosarcoma, suggesting that H2-M3 was needed to fight cancer in these models. When CD8+ T cells were depleted, no difference in lung metastases were noted, but when NK cells were depleted, much higher rates of lung metastases occurred, which suggests that NK cell activity was central to the antitumor response. The authors determined that H2-M3 was needed in Ly49A positive cells to license NK cells to full effector function. Indeed, depleting Ly49A cells increased lung metastasis. Performing bone marrow transplant of donor cells from an H2-M3–deficient mouse resulted in more rejection than transplant with control donor cells and was abrogated by antibodies against Ly49A and NK cells. Taken together, these studies establish H2-M3 as a “missing-self” determinant, needed for tolerance. These findings reveal a new mechanism for establishing self-tolerance and for licensing NK cells that may be relevant to humans, who also express noncanonical HLA molecules. That noncanonical MHC I and its counterparts in humans are differentially expressed on tissue is intriguing, and distinct from classical MHC I, which is expressed ubiquitously. The relevance of tissue-specific expression of these molecules remains to be determined. A window of therapeutic opportunity may be revealed by better understanding the role of noncanonical MHC in mediating self-tolerance and protection against cancer and infection. D. M. Andrews et al. , Recognition of the nonclassical MHC class I molecule H2-M3 by the receptor Ly49A regulates the licensing and activation of NK cells. Nat. Immunol. 13 , 1171–1177 (2012). [[Abstract]][1] [1]: http://www.nature.com/ni/journal/v13/n12/full/ni.2468.html