Immune responses to infectious or damaging agents are commonly categorized as being mediated either by the innate arm of the immune system or the adaptive arm of the immune system. The innate immune system is distinguished from the adaptive immune system in that it uses a finite number of germ line encoded receptors to sense pathogens and tissue damage. Innate immune responses are not selected for high affinity interactions between immune cells or pathogens and do not lead to immunological memory. In contrast, the adaptive immune system relies on non-homologous end-joining and chromosomal DNA recombination in a recombinase activating gene (RAG)-dependent manner to generate T and B cell receptor repertoire that recognize a vast number of different antigens. Activation of T and B cells by their specific antigen leads to the selection of high affinity effector and memory cells, resulting in accelerated and enhanced, antigen specific recall responses upon challenge, another hallmark of the adaptive immune system.
Adaptive immune responses occur to a variety of antigens, including infectious pathogens and non-infectious substances, and even organic or inorganic molecules, such as 2,4-dinitro-1-fluorobenzene (DNFB) and 4-ethoxy-methylene-2-phenyl-3-oxazalin-5-one (OXA). These so called haptens form covalent bonds with amino acid side-chains of self-proteins, and are recognized as altered-self by the immune system. DNFB and OXA are classic examples of contact sensitizers that elicit delayed type hypersensitivity (DTH) responses, specifically hapten-induced contact hypersensitivity (CHS). Typically, the first exposure to hapten results in sensitization, while a second exposure to the same hapten triggers an adaptive immune response, associated with tissue swelling at the site of challenge caused by the recruitment of inflammatory cells.
Until recently, there has been no evidence that any types of cells other than T and B cells could give rise to adaptive immune responses, characterized by antigen specificity and memory, in mammals. However, it has now been demonstrated that mice devoid of T cells and B cells can demonstrate substantial contact hypersensitivity (CHS) responses to haptens (O'Leary et al. 2006. Nature Immunology 7:507). These CHS responses were found to be both adaptive and antigen specific. Mice lacking all lymphocytes, including natural killer cells, did not display CHS responses. Adoptive transfer experiments demonstrated that the hapten-specific memory in the mice lacking T and B cells resided in a Ly49C-I+ natural killer subpopulation localized specifically in the livers of the animals.
Further information regarding the capacity of NK cells to mediate adaptive immune responses, the types of antigens to which they can mount antigen-specific responses, and the signals required to mediate such responses will be of tremendous benefit in controlling antigen-specific NK cell responses. Knowing this information will allow, inter alia, for augmentation of antigen-specific NK cell effector function in subjects that would benefit from increased NK cell activity, e.g., in immunodeficient subjects, as well as reducing antigen-specific NK cell effector function in subjects that suffer from unwanted immune system activation, e.g., in the case of CHS responses.