Functional role of human natural killer cell receptor 2B4 (CD244) isoforms

Abstract

Natural killer (NK) cells are a subpopulation of lymphocytes that represent the first line of defense against stressed, virally infected and malignant cells. NK cell functions are controlled by a balance between positive and negative signals through various receptors. We have identified, cloned and characterized the 2B4 (CD244) receptor in mice and human. 2B4 interaction with its ligand CD48 regulates NK, T and B cell functions and thus plays an important role in various immune responses. Human NK cells express two isoforms of 2B4, h2B4‐A and h2B4‐B that differ in a small portion of the extracellular domain. In the present investigation, we have studied the functions of h2B4‐A and h2B4‐B. Our data demonstrate that these two isoforms differ in their binding affinity for CD48 and this result in differential cytotoxic activity by NK cells against tumor targets. h2B4‐A was able to mediate natural cytotoxicity against CD48 expressing K562 target cells confirming that h2B4‐A is an activating receptor, whereas h2B4‐B showed no effects. Analysis of the predicted 3‐D structure of the two isoforms showed conformational differences which may be responsible for their differences in binding affinity to CD48. Thus differential expression of 2B4 isoforms by NK cells may regulate immune response mediated through 2B4‐CD48 interactions. This work was supported by the NIH grant CA85753.