Peptide-adaptive NK cell memory in the absence of functional TCR genes

Natural killer (NK) cells are a key component of the innate immune system and are specialized in the recognition and elimination of virally infected, tumor, and otherwise abnormal cells. However, multiple laboratories have shown that NK cells display exquisite MHC-I-dependent memory toward haptens, complex proteins, and peptides in mice lacking RAG proteins, which are devoid of both T cells and B cells but still have intact TCR genes, in addition to abnormal NK cell expansion and activation. Here, we show that the fine antigen specificity of memory NK cells persists in the absence of functional TCR genes. The ability of NK cells to mediate adaptive responses was evaluated using contact hypersensitivity (CHS) responses to chemical haptens and peptides in TCR-β-/-δ-/- mice. Peptide specificity and memory was maintained in these mice as shown by CHS after sensitization with multiple unrelated peptides individually or as a mixture. This was done in conjunction with depletion of key immune subsets including all NK cells, Ly49C/I+ NK cells, or B cells. In the absence of NK cells, and specifically Ly49C/I+ NK cells, TCR-β-/-δ-/- mice were unable to exhibit immunological memory responses, similar to what was previously reported for Rag1-/- mice. Furthermore, depleting B cells did not impact TCR-β-/-δ-/- mice's ability to exhibit adaptive immune responses. These findings highlight and reinforce the capability of NK cells to form adaptive memory responses to peptides in the presence or absence of T cells, and without the need for functional TCR genes.