Adaptive immunity depends on the presence of B cells and T cells. Or does it? Now von Andrian and colleagues show that in the classic example of adaptive immunity, the hapten-induced contact hypersensitivity (CHS) response, hepatic natural killer (NK) cells can mediate antigen-specific, long-lived adaptive recall responses independently of B cells and T cells.

A widely used model of CHS involves sensitization of mice by painting the hapten 2,4-dinitrofluorobenzene (DNFB) on to the dorsal skin, followed by challenge with DNFB at a remote location (such as the ear) several days later. Challenge after sensitization induces a local hapten-specific recall response that has previously been associated with αβ T cells, γδ T cells and B1 cells. However, O'Leary et al. found that the magnitude of the sensitization-dependent recall response was identical in recombination-activating gene 2 knockout (Rag2−/−) mice, which are completely devoid of B cells and T cells. They also found that the immune response to hapten in these Rag2−/− mice was inducible, long-lived and antigen-specific, all of which are functional hallmarks of adaptive immunity.

Several observations indicated that the most probable cell type involved in this B-cell- and T-cell-independent CHS response was NK cells. Therefore, to confirm the role of this cell type, NK cells were depleted from Rag2−/− mice using asialo-GM1-specific or NK1.1-specific antibody. These mice, when challenged with DNFB following sensitization, had completely lost the ability to mount a CHS response.

To further confirm these findings, sensitized NK cells were adoptively transferred to naive mice that were deficient for both RAG2 and the common cytokine receptor γ-chain. These mice, in addition to being B-cell- and T-cell-deficient, also completely lack NK cells. Subsequent challenge with DNFB resulted in a vigorous CHS response in these mice, confirming the ability of sensitized NK cells to mediate a hapten-specific memory response independently of B cells and T cells. These transferable hapten-specific NK memory cells were shown to localize in the donor's liver but not in the spleen.

These results describe an unexpected function for NK cells and indicate that a B-cell- and T-cell-independent adaptive immune response exists in mammals.