Killer Cells: An Offensive Defense

When scientists realized that the immune system could discriminate self from non-self, they began to study whether the body could recognize tumor cells as foreign and then eliminate them. An immune response against foreign antigens (for example, viruses or bacteria) typically requires immunization and also that the foreign antigen binds to the body's own major-histocompatibiity [MHC] antigens (for example, HLA or H-2). Using in vitro assays to measure the killing of tumor cells, researchers found that certain lymphocytes (a type of white blood cell responsible for recognizing foreign antigens) could lyse, or destroy, tumor cell targets. Surprisingly, these unique lymphocytes are present in the blood of normal, unimmunized individuals and they are able to recognize tumor cells that do not carry self MHC markers. The lack of requirement for immunization, and the ability to recognize tumor cells without MHC antigens, provided a working definition for a new type of cytotoxic, or killer, lymphocyte, the NK cell. Moreover, these unusual functional properties distinguished NK cells from conventional cytotoxic T lymphocytes, which can only attack cells after immunization and which recognize antigens only in the presence of MHC gene products. For several years, it was uncertain whether NK cells were a distinct type of lymphocyte or simply T lymphocytes that killed in a different "nonspecific or promiscuous" manner. This issue was resolved only recently at the 5th International Workshop on Natural Killer Cells (Hilton Head, S.C., March 22-25, 1988). Researchers now agree that NK cells constitute a third major population of lymphocytes, distinct from both T and B lymphocytes. This third type can be defined by antigenic, molecular genetic, and functional criteria. First, NK cells are granular lymphocytes that do not rearrange or productively express the T-cell antigen receptor (alpha, beta, gamma, or delta) genes. They can be positively identified by expression of certain cell-surface differentiation antigens, for example, in man, the CD16 (Fc receptor type III) and/or the Leu 19 (NKH-1) antigens. Second, they recognize and lyse tumor cells and certain virus-infected targets even when MHC antigens are not present on the plasma membrane of the target. And third, they are largely responsible for antibody-dependent cellu- lar cytotoxicity mediated by lymphocytes, and are the predominant effectors of the lymphokine-activated killer phenomenon, that is, the killing of solid tumor-cell targets by human peripheral blood lymphocytes stimulated in vitro with interlukin-2. Finally, NK cells apparently come from bone marrow and, unlike T lymphocytes, do not require the thymus for differentiation and maturation. Although NK cells are predominantly responsible for "natural killing” activity, some T lymphocytes may also be involved. Whether these cytotoxic T lymphocytes exhibiting NK-like activity recognize tumor cell targets via their T- cell antigen receptors, or alternatively, use another recognition structure also expressed by NK cells, is currently under investigation by several laboratories. The major outstanding question in the field is: How do NK cells recognize malignant or virus-infected cells? Although several molecules have been shown to be involved in the cellular adhesion necessary for NK cell-mediated cytotoxicity, the structure(s) involved in actual self/non-self discrimination has not been identified. Since NK cells do not possess the exquisite antigenic specificity of T and B cells, it is unlikely that an "NK target receptor" will demonstrate the potential for diversity shown by immunoglobulins and the T-cell antigen receptors. As yet, it is uncertain whether NK cells use a single receptor or several types of receptors for recognition. The structures on tumor cells and virus-infected cells that are recognized by NK cells have not been identified. The tools of hybridoma technology and molecuIar biology should resolve this issue soon. What is the physiological role of NK cells? Although most laboratories have focused on the ability of NK cells to kill tumors, it is uncertain whether NK cells evolved to protect against malignancy. Rather, NK cells may play a vital role in the primary defense against some, but not all, viruses. NK cells are important in the primary antiviral defense that occurs during the first few hours or days after infection. In animal model systems, certain viral infections are lethal if NK cells are removed. These NK cell-depleted animals do generate a normal primary cytotoxic T cell-mediated response; but without the early elimination of a substantial proportion of virus-infected cells by NK cells, the disease is often fatal. These data indicate that NK cells serve as primary defenders against certain viral infections. NK cells probably do not act in isolation, but affect the function and perhaps development of other cell types For example, tumor cells, virus-infected cells, bacterial products, and immune complexes can induce NK cells to secrete lymphokines, including tumor necrosis factor and gamma-interferon. These in turn can indirectly affect the activity, of other lymphocytes and myeloid cells. NKcells have been implicated in regulation of bone marrow hematopoiesis and in host-versus-graft disease subsequent to bone marrow transplantation, although the mechanisms of these phenomena have not been delineated. It is now recognized that NK cells are a distinct cell type acting with B and T cells to comprise the predominant lymphoid effectors of the immune system. Lewis L. Lanier is a research scientist at Becton Dickinson, Immunocytometry Systems, Mountain View, Calif.

Killer Cells: An Offensive Defense

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