Antigen-Adaptive NK Cell Memory In The Absence Of Functional TCR Genes

Abstract

Natural killer (NK) cells are among the founding members of innate lymphoid cells, specialized in the recognition and elimination of virally infected cells, tumour cells, and abnormal cells. Recent research studies have uncovered that NK cells also exhibit adaptive immune features similar to T and B cells, which holds promise for using the NK cell memory for the development of new cancer and viral immunotherapies. Research in our lab demonstrated that NK cells can elicit immunological memory in Rag1-/- mice, which are devoid of the adaptive T cells and B cells. However, there remains a need to explore whether this phenomenon persists in the complete absence of TCR genes. The ability of NK cells to mediate adaptive responses was evaluated by studying the contact hypersensitivity ear swelling response to chemical haptens and peptides in TCR-β-/-δ-/- mice. This was done in conjunction with NK cell depletion via anti-NK1.1, Ly49C/I+ NK cell depletion via anti-Ly49C/I, and B cell depletion via anti-CD20. In the absence of NK cells, specifically Ly49C/I+ NK cells, TCR-β-/-δ-/- mice were unable to exhibit immunological memory responses. Furthermore, depleting B cells did not impact TCR-β-/-δ-/- mice’s ability to exhibit adaptive responses. It was essential that mice be sensitized and challenged with the same hapten or peptide in order for NK cell memory responses to be observed. These results show memory responses can be attributed to NK cells in the absence of TCR genes and is antigen-specific. This study shows that NK cells are a physiologically relevant contributor to the adaptive immune response as immunological memory can be observed in the absence of TCR genes. A better understanding of the adaptive NK cell responses elicited in these studies can be exploited in therapeutic and prophylactic treatments of cancer and viral infections.