自然弒細胞發生學的雙系模式：白血球介質15及21分別導引 CD56+Kir±lectis+ 弒細胞 及CD56±Kirlectin自然弒細胞(1/3)
Date Issued
2003
Date
2003
Author(s)
許世明
DOI
912314B002179
Abstract
NK-cell development depends on interleukin 15, as shown by the complete absence
of NK-cells in transgenic mice knocked out for either interleukin 15 or its receptor.
However, mature human NK-cells in the peripheral blood differ from mouse NK-cells,
with varying expression of surface NK-markers, such as CD56, C-type lectin, and
KIR, and secretion of type I and type II cytokines. It is still unclear how the
expression patterns of CD56, C-type lectins and KIRs are related to each other
and to their functions, type I vs type II.
NK-cells and T-cells arise from a common CD44+, CD25-, CD161+ bipotent T/NK precursor,
which subsequently diverges into T-cells under interleukin 7, Notch and E2A, or
alternatively into NK-cells under interleukin 15 and Id3. Id3 and E2A are both
helix-loop-helix transcription factors, whereas interleukins 7 and 15 have a
4-a-helical-bundle structure using a common g-chain (gc) in their receptors. For the
study of NK-cell development, we propose to isolate from bone marrow, thymus, or
peripheral blood by flow cytometry the common bipotent CD44+, CD25-, CD161+,
gc +, T/NK cells. They will be positively selected for interleukin 15 receptor and Id3,
and negative selected for interleukin 7 receptor and E2A. We will then use a
developmental approach to support, clarify, or refute previous
functional-structural studies on 3 issues.
(I) CD56 brigtht vs CD56 dim . Human NK-cells could be divided into a CD56 brigtht
subset and a CD56 dim subset. Based on functional characterization (Natur e 2000) that
showed expansion of CD56 dim NK-cells under interleukin 21, we want to show that
NK-cell precursors will develop into either the CD56 brigtht subset in the presence of
interleukin 15 or the CD56 dim subset in the presence of interleukin 21.
(II) Type I vs Type II. In the classical dichotomy model, a common type zero NK
cell will give rise to either type I NK cells secreting predominantly IFN-g and type II
NK-cells secreting predominantly interleukin 4 and interleukin 13. However,
functional analysis (Nature Immunology 2001) seems to indicate a type II-type
0-type I sequence. We will clarify the dichotomy vs sequential controversy by tracing
back to the common bipotent precursors.
(III) C-type Lectin vs KIR. Human NK-cells use both C-type lectins and KIRs as
antigen receptors that recognize different structures of the MHC-1 molecules (Trends Immunology, 2001). We want to show that C-type lectin might represent a more
primitive less specific antigen receptor earlier in the development of NK-cells.
Using a developmental approach, we want to integrate previous
functional-structural data into a dual lineage model for the development of mature
human NK-cells in which interleukin 15 and interleukin 21 drive r espectively the
development of CD56 brigtht KIR dim Lectin bright type I (IFN-g+) NK-cells and
CD56 dim KIR bright Lectin dim type II (IL-13+) NK-cells. This model can then be
applied to the study of sinonasal lymphoma, which is an EBV-associated NK-cell
lymphoma rather common in Taiwan, and might contribute to the clinical
management of these patients.
Subjects
Developmental biology
NK-cells
IL-15
IL-21
KIR
C-type lectin
Publisher
臺北市：國立臺灣大學醫學院免疫學研究所
Type
journal article
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