From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: Natural Killer Cells
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6722
Organization: unspecified
Date: Wed, 6 Jan 93 09:02:26 PST

                      NATURAL KILLER LYMPHOCYTES

Chapter 1 Principles of Tumor Immunity: Biology of Cellular Immune 
Responses by John R. Wunderlich and Richard J. Hodes. The book is 
"Biologic Therapy of Cancer" (1991) edited by Vincent T. DeVita, Jr., 
Samuel Hellman and Steven A. Rosenberg; published by J.B. Lippincott 
Company.

Pages 12-14

MHC-DEPENDENT, ANTIGEN-SPECIFIC CYTOTOXIC EFFECTOR CELLS

NATURAL KILLER LYMPHOCYTES

Natural killer (NK) lymphocytes do not result from a classic cellular 
immune response. They are cytolytically active in a nonspecific fashion 
when taken from an unimmunized host. Target-cell recognition is not 
restricted by MHC. The NK cells do not express TCR, and they do not 
depend on the thymus for maturation. There is no memory response by NK 
cells following reexposure of the host to a reactive target.

The NK cells are large granular lymphocytes that do not have rearranged 
genes for the TCR. They appear to originate and perhaps differentiate 
initially in the bone marrow. They are either in a cell lineage separate 
from that of CTLs or they diverged from the T-cell lineage at an early 
prethymic stage. The identity of the inactive precursors of NK cells and 
the activation signals that contribute to their maturation are not 
known. The use of cell-surface markers or phenotypes to identify NK 
cells has inherent problems, because many of the markers may indicate 
the state of cell activation rather than lineage. However, several 
markers are particularly helpful in distinguishing between NK cells and 
CTLs. The distinction between NK cells and NK-like activity is 
important. As discussed below, CTLs cultured with IL-2 can exhibit 
NK-like activity, but they are not NK cells. Moreover, a small subset of 
human peripheral-blood lymphocyte (PBL) T cells, which are CD56+, can 
mediate MHC-nonrestricted cytotoxicity. Human NK cells, unlike CTLs that 
are cytotoxic in an MHC-restricted fashion, express CD56 antigens. In 
contrast to most CTLs, NK cells also express a surface receptor for 
immunoglobulin (FcR) and are efficient mediators of antibody-dependent 
cellular cytotoxicity. The FcR triggers the release of cytotoxic 
mediators from NK cells when cross-linked by antibody bound to target 
cells. Thus, human NK cells are CD3-, CD56+, FcR+. These cell-surface 
features have been used both for physically separating the cells and for 
functional distinction between NK-cell and CTL activity.

Although the picture is far from complete, the basic cytotoxic 
mechanisms of NK cells and CTLs appear to be similar. Like CTLs, NK 
cells depend on surface adhesion molecules for binding to target cells. 
In both cases, cell binding is followed by target-cell lysis and then 
detachment and recycling of the effector cell. Cytolysin/perforin and 
members of the lymphotoxin family have well-established roles in 
NK-mediated cytotoxicity.

The NK cells are not specific to target cells. Nevertheless, they 
exhibit two levels of target-cell selectivity. First, they are more 
toxic for tumor cells, virus-infected cells, and cultured cells than for 
most normal cells. Second, different clones of NK cells show different 
patterns of cytotoxicity with panels of tumor cells from different 
sources. Thus, NK cells can select target cells from among different 
sources of tumors. This characteristic of NK cells could result from a 
family of different triggering receptors for target cells, a possibility 
currently under investigation. Neither the NK-cell receptors nor the 
target-cell ligands that trigger cytotoxicity have been identified.

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