Breakthrough Advances in Natural Killer (NK) Cells Over 50 Years

Since the first reports of lymphocytes exhibiting "non-specific" killing of tumor cells in 1973, the understanding and significance of Natural Killer (NK) cells have evolved immensely. In 1975, Rolf Kiessling and colleagues at the Karolinska Institute coined the term "Natural Killer" cells, highlighting their unique ability to spontaneously attack tumor cells without prior sensitization.

Over the next fifty years, numerous laboratories worldwide have extensively studied NK cells in vitro to elucidate their role in host defense against tumors and microbial pathogens, as well as their regulatory functions within the immune system.

NK Cells: The Pioneering Innate Lymphocytes

NK cells, the first characterized members of the innate lymphocyte family, defend against tumors and pathogens through direct cytotoxic activity and secretion of cytokines and chemokines. Initially referred to as "null cells" due to the absence of identifying markers, advancements in single-cell RNA sequencing, flow cytometry, and mass spectrometry have allowed detailed classification of NK cell subtypes.

The First Decade (1973-1982): Discovering Non-Specific Cytotoxicity

The late 1960s and early 1970s saw the development of simple in vitro assays to measure cell-mediated cytotoxicity. In 1974, Herberman and colleagues demonstrated that peripheral blood lymphocytes from healthy individuals could kill various human lymphoma cells. Kiessling, Klein, and Wigzell further described the spontaneous lysis of tumor cells by lymphocytes from non-tumor-bearing mice, naming this activity "natural killing."

The Second Decade (1983-1992): Phenotypic Characterization and Viral Defense

During the 1980s, the focus shifted to the phenotypic characterization of NK cells, leading to the identification of subpopulations with distinct functions. By 1983, scientists had identified functionally different subsets of human NK cells. Further studies highlighted NK cells' crucial role in defending against herpesviruses, exemplified by a patient with severe herpesvirus infections due to a genetic NK cell deficiency.

The Third Decade (1993-2002): Understanding Receptors and Ligands

Significant progress in the 1990s and early 2000s led to the identification and cloning of NK cell receptors and their ligands. Discoveries such as the NKG2D receptor and its stress-induced ligands established a foundation for understanding NK cells' "altered-self" recognition mechanisms.

The Fourth Decade (2003-2012): NK Cell Memory and Licensing

Contrary to traditional views, studies in the 2000s demonstrated that NK cells could exhibit memory-like responses. Researchers showed that NK cells could mediate antigen-specific responses and develop a form of "memory" akin to adaptive immune cells. Additionally, the concept of NK cell "licensing" emerged, explaining how interactions with self-MHC molecules could enhance NK cell responsiveness.

The Fifth Decade (2013-Present): Clinical Applications and Diversity

In the last decade, technological advancements have driven NK cell research. Mass cytometry and single-cell RNA sequencing revealed extensive phenotypic diversity among NK cells. Clinically, NK cells have shown promise in treating hematologic malignancies, as demonstrated by the successful application of CD19 CAR-NK cells in lymphoma patients in 2020.

Future Prospects: Unanswered Questions and New Horizons

As research continues, several intriguing questions remain. How do NK cells acquire antigen-specific memory? Can NK cells be harnessed to control autoimmune diseases? How can we overcome the challenges posed by the tumor microenvironment to activate NK cells effectively? The next fifty years promise exciting and unexpected discoveries in NK cell biology, offering new therapeutic strategies for cancer and infectious diseases.