Memory response of Natural Killer cells

The beauty of our immune system lies in the diversity of the cells involved in the responses triggered by a range of pathogens. These responses can be broadly classified into two groups: innate immune response, which is mainly a non-specific first line of defence, and adaptive immune response, which is acquired over the lifetime of all vertebrates and contains highly differentiated cells that are specific to the antigen. These cells are capable of recognizing the antigens upon secondary exposure and therefore contribute to the memory of the immune system.

Until now, natural killer (NK) cells were considered to be a significant part of the innate immune system participating in non-specific responses. These cells play important functional roles against tumor cells and virus infected cells, through their cytolytic activity. Like T and B cells of the adaptive immunity, NK cells do not express RAG (recombination-activating gene) proteins that are required for assembling the antigen specific receptors on the cells. Based on this concept, RAG knockout mice are common model organism to study cell-mediated immune responses as they lack a functional adaptive system.

Figure 1 - Rag1/2 knockout mouse lacks memory
Figure 1 – Rag1/2 knockout mouse lacks memory

Contact hypersensitivity (CHS) is another significant experimental model used to study cell-mediated immune function in the context of memory.1 In this, epidermal cells that are exposed to haptens (compounds that modifies proteins and elicit an immune response) exhibit a delayed-type hypersensitivity reaction. It was first shown by O’Leary et al.2 that Rag2 knockout mice exhibited hapten induced CHS due to NK cells, thus confirming the role of NK cells in memory responses.

Figure 2 - Hapten induced Rag2 knockout mouse exhibited CHS
Figure 2 – Hapten induced Rag2 knockout mouse exhibited CHS

So how did O’Leary et al. confirm that it was indeed NK cells that was responsible for inducing hypersensitivity and not other cell types of the innate immune system? As shown in Fig. 2 above, Rag2 knockout mouse that is incapable of producing mature T and B cells still reacted to the hapten. However, Rag2/II2rg double knockout mice did not exhibit the hypersensitivity reaction when exposed to haptens. These double knockout mice lack NK cells along with T and B cells. Moreover, the Rag2 deficient mice that were treated with anti-NK 1.1 antibody (binds to receptors on NK cells and prevents activity) also showed no hypersensitivity response to the haptens. The wild type mice treated with anti-NK 1.1 antibody exhibited CHS due to the activity of T and B cells.

The study of immune responses is still a new and exciting field with many unanswered questions and unknown terrains yet to be discovered. This novel insight on NK cells possessing adaptive immune-like responses and its role in memory could be significant in designing next generation vaccines against a range of pathogens.


  1. Gaspari AA, Katz SI. Contact hypersensitivity. Current Protocols in Immunology. 2001 Chapter 4, Unit 4 2.
  2. O’Leary, J.G. , Goodarzi, M. , Drayton, D.L. & von Andrian, U.H. T cell- and B cell- independent adaptive immunity mediated by natural killer cells. Nature Immunology. 7, 507–516 (2006).

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