IMMUi’dOLOGY TODAY

cells and reproduction I Ashley King, Yung Wai Loke and Gerard Chaouat

role in the regulation of hemat”p”~tzG,

where then effects are exert4 bv cytokiw

prudurtion. Another ‘homtwstatlc’ role for

NK celk may be in wpmduchon and the con-

trol of ptact?Wi”n, ds Nk cells arr ah.mdant

at the implantabon bee 1~ many spexr.

Uterine NK cells

have pmminent cyt”plnsmr granultsand arc

crpab!? of luvv spontanmw cytolytic actinty.

They are readily actwzted by interlakm 2

(iL-2) and can then kdl tropimblast cells.

In rodents, a utenne ~ru~hme known as

the metrial gl;nd -a group “f cells ihat pm

liftvateand Jlfferentmtt~in the mu~;e”t the

metrial rriangle - appears mldway through

get&w”. Phewtypic characteruation has

assigned ihcw cell5 to the NK Imrage: I” the

mouse, they rxpres- as&-CM,, NKI.1 and

LGL-1; and. in the rat, they express NKR-PI

and Tt’rforrn but not Convenhonal T-cell,

B-cell or macmphage markers. Some of

these markers (e.g. LGL-I and NKR-PI) ap-

pear to be downregulated as gestation pro-

cexis and as the c&s mahxe and become

more granulated

In humans, the pred”minar.t uterine

lymphocytes m early g&ahou arc CDS6’=@

granulated NK celk that do not express

CD16 or membrane CD3, and account for

-707 of bone-marmwderivtd cells. Human

~:tenne NK cells therefore phenotypically TP

wmble teed NK cells and 10% of cimdahng

adult NK <ells.

The relahonship of hss”e uterine Ntc

cells t” circulating NK cells is unclear, and it

IS unknown when :he ,xcanors seed to the

uterus. The factors controlling the influx,

proliferahon and differentiabon of these

c&s m the utem.5 are also unkn”*.m but, m

rodents and humans, these processes seem , to be dependent on decidualiihon of the

stromal cells.

NK-cell ontogeny Elegant experiments analyzing the “rigm of

NK cells early in ontogeny 0. Phillips, Palo

__‘_ /

IMM’JNOLOGY TODAY

41to. CA) have shown that NK cells can b+

generated under spec~hc clomng conditions

from CD4 CD8 CD3 ‘hipie-ncgatwe’ cells

that expwss CDUb*, CD5- and cytoplar

mrc CD3e- from all fetal hematopoletic hs

sues inciodmg the thy”xus. These CD34h@”

cells can be induced to develop into T cells

under differolt cloning conditions and may

reprmt the brpowntial NK/T pmgemtor

cell.

a ciass I probe revealed a novel class I allele

Pvtamu-AC) that IS related to human HLA-A

and encodes the shortened cytoplasmlc do

m;lin and altenwtive sphce variants typical

of HLA-G. This finding emphastzes the

+wcIes spnfidty that *s chxxterrstic of

nonckssical class I genes

NK-cell biology in the past year, there has been a flurry of

mfonnation on the shuchwe and funcho” of

NK-cell rxeptors for MHC class I molecules

as well as for other, unk”.wn, hgands.

Recent data were reviewed at this meeting.

The similarhies hehveen the kilier-cell

Inhibitory receptors (KIRs) in humans and

the munne Ly-49 famdy were emphasizedi.

fitthough KlRs beIo”g to the immuno-

globulin (Ig) superfamily and Ly-49 mol-

ecules are type II membrane protei”s with a

C-type lectin, KIRs and Ly-49 family mem-

bers are expressed selectiveiy by overlap

ping subsets of NK ceils. They both exhibit

a Ixx”isc.zms specifiaty for ciass I mol-

erules, recognizing primordial polymor-

ph&ns. In general. they de!iver m ?“-

hibrtory signal blockmg NK-ceII activation.

A search for the respective counterparts in

mouse 2nd humans using degenerative

pol~erase cham reaction (I’CR) has found

the mouse KIR gp49 Thrs has hvo Ig-like

domains :nd a” immunoreceptor tyrosi:w

based activation motif (ITAM, I” the cyto-

plasmic domam, but rt is not known

whether it bmds MHC class I mokxmes

W. Yokoyama, St Louis, MO)‘.

Several featmes of Ihrse NK-cell nxep-

tars for class I molez-ules are of interest to

repmduchve biologsts. Different humen

mdividwls and mouse strain= have chstinct

repertowes of receptors, and these are

genehcally mherited (A. Moretta, Cenova).

Furthermore, receptors for nonself MHC

class I hgands are found, which must be

capable of allorecogrddon” Obviously, pug-

nancy is a unique natural scenano where

allorecog”itIon occurs physiologxxlly. The

d-dual NK cells m humans express the

same members of the KiR famdy as NK cells

I” peripheral blood (5. Hiby, Cambridge,

UK) and the repertoire varies between dif-

ferent mdividuals but, interestingly, this

repertoire is different from that of the

NK cellt. m blood from the same rndividuai

(S. Vetma, Cambridge,, UK) Thus, Imman

maternal uLnne NK cells do have a me&c

msm to recognize fetal tmphobiast chss I

molecules. The NK-celI effector mechanisms

are obscure, especrdly as KIRs and activa-

tory forms lacking the cytoplasmic ITAM

domains (KARsj have both been found.

Similar studies on Ly-19 expresslo” on

mmine utenne NK cells, together with elud-

d&lo” of murine tmphoblast MHC class I

expression, are eagerly awaited.

The 4-49 genes are encoded 1” a region

known as the NK gene complex where se’.-

era1 NK-asmated genes wtth irain-like

stmctores are found. The gene encoding

CD94 is found in the equivalent region in

humans. CD94 is hmctionafly ambivalent,

but when present at high levels I! deIivft-5

an inhibitory slgwal on recognition of a broad

range of HLA class I molecules7. CD94 x-

curs as part of a hcte;zIi!im.~ ic.xpr.:ing

subunits of 43 kDa and 39 kDa), but itseuct

molecular shuctore IS still uncle&. CD94 Is

of particular interest m the “terns as 11 is

expressed at high levels by aII CD%**’

cel!s :” the dccidua and recogntzas HLA-G

(M. Ldpez-Rot&, Madrid).

Signaling events in NK cells were also

reviewed (E. Vivier, Marseille; A. Santom,

Romc~. The cytoplasnuc domam of the KiR

contains a characteristic form of ITAM [now

designated immunoreceptor tymsine-based

Inhibitory motrf (ITIM)] with a distinct “um-

ber of spacer amino acids (26 atmno acids in

KIRs). This delivers an inhibttory sign31 by

recrmtmmt of protein tymsnw phosphatase

If (MT’-IC) and MI’-ID (Ref. 9). Signaling

via other NK receptors such as CD16 and 6,

mtegrins was also discussed The finding that

adheson molecules can act as co-receptors

to KIRs may be parhcularly relevant to the

function of uterine NK cells l&sue uterine

NK ce!Is migrate over a dense hormonally

regulated extracellular matrix rich I,, fibro-

wr!:n and laminin hbronectin and Iaminin

were mported to support NK-celI migration,

this being media& by oi and IQ mtrgrins

(K. Sommersalo, HelsinW.

Animal models _I v>g:i . irig the effects on placentaho” of de-

pleting the uterine NK cells is an obvious

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