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Journal of Clinical Immuno logy Vol . 13 N o. 2 1993
C han ges of Na tural K i ller C el ls During cu tePsycholog ica
l StressMANFRED SCHEDL OWSKI, 1 4 ROLAND JACOBS, 2 GERTRUD
STRATMANN, 2 STEFANRICHTER, 3 ANDREAS HADICKE , 3 UWE TEWES, I
THOMAS O. F. WAGNER, 3 and REINHOL D E.SCHMIDT2
A c c e p t e d : O c t o b e r 23 1 9 92
Emotional stress is often followed by increased suscepti-bility
to infections. One major role in the immediateimmune response to
infection is played by natural killer(NK) cells. This study was
designed to establish whetheracute psychological stress influences
cellular immunefunctions and to elucidate the role of endocrine
parame-ters as potent mediators of stress induced alterations ofthe
immune system. Forty-five first-time tandem para-chutists were
examined continuously for their plasmaconcentrations of cortisol
and catecholamines from 120min before to 60 min after jumping.
Lymphocyte subsets,NK activity, and ADCC were determined 2 hr
before,immediately after, and 1 hr after jumping. There was
asignificant increase in sympathetic-adrenal hormones dur-ing
(adrenaline, noradrenaline) and shortly after jumping(cortisol).
Lymphocyte subsets and the functional capac-ity of NK cells
revealed an increase immediately afterjumping followed by a
decrease significantly below start-ing values 1 hr later. These
changes were significantlycorrelated to plasma concentrations of
noradrenaline.Thus, quick mobilization of NK cells is suggested as
onemajor mechanism for this effective adaptation of theimmune
system to stress situations.K E Y W O R D S Stress; natural killer
cells; catecholamines;cor-tisol; parachute
umping.INTRODUCTIONStress has been suggested for a long time to
beassociated with a decrease in natural killer (NK)1Division of
Medical Psychology, Medizinische HochschuleHannover, Posffach61 01
80, 3000 Hannover 61, FRG.2Division of
Immunology,MedizinischeHochsehuleHannover,Postfach 6l 01 80, 3000
Hannover 61, FRG.3Division of Endocrinology, Medizinische
Hochschule Han-nover, Postfach 61 0t 80, 3000 Hannover 61, FRG.4To
whom correspondence should be addressed at AbteilungMedizinische
Psychologie, Medizinische Hochschule Han-hover, Postfach 61 01 80,
3000 Hannover 61, Germany.
activity. There is also accumulating evidence
frompsychoneuroimmunological research (1) that stresssituations
such as examination (2, 3) or bereave-ment (4) may alter a wide
range of immunologicalfunctions, especially NK cell function.
Moreover,increased incidences of viral infections or cancerhave
been reported in stressed populations (5, 6).
NK cells are believed to act early in the immuneresponse, before
specificity can be generated, andrepresent approximately 12-15% of
peripheralblood lymphocytes (7-9). They mediate first-linedefense
by direct cytotoxici ty against various typesof target cells
without apparent prior immunization(10). More recently they have
been characterizedphenotypically as coexpressing the cell surface
an-tigens CD16 and CD56 and lacking the CD3/TCRcomplex (11). NK
cells have also been demon-strated to play an important role in the
immunesurveillance against tumors and virally infectedcells (9,
10). Other reports have shown that NKcells represent a subse t of
peripheral blood lympho-cytes which quickly respond to activation
signalssuch as interleukin-2 (IL-2) via the respective cyto-kine
receptors i n v i v o and i n v i t r o (7, 12). I n v i t r
ostimulation of NK cells with high concentrations ofadrenaline
causes a decrease in NK function. Incontrast, lower concentrations
appear to increaseNK activity (13). I n v i v o administration in
humansalso induces an increase in NK activity with a rapiddecrease
during follow-up (t4, 15). Other i n v i v odata in humans during
physical stress reported anincrease in NK activity after exercise
(16-i8).These observations together with data demonstrat-ing that
lymphocy tes express receptors for a varietyof hormones (19)
suggest that various neuroendo-crine parameters may influence NK
activity in
1190271-9142/93/0300.0119507.00/0 993 Plenum Publ ishing
Corporat ion
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12 S HEDLOWSKI E T A L .
pe r iphe r a l b lood . W he the r psy c ho log i c a l s tr e
s s i si n f lue nc ing pe r iphe r a l b lood lym pho c y te s a
nd , i npa r t i c u l a r , NK c e l l s a nd whic h hor m one s a
r e i n -v o l v e d h a v e n o t b e e n e s t a b l i s h e d y
e t , s i n c e t h em a n i p u l a t i o n o f t h e s y m p a t
h e t i c -a d r e n a l s y s t e m invivo has remained di f f
icul t .I n o r de r t o a na lyz e phys io log i c a l pa r a m e
te r s suc ha s h o r m o n e s a n d a l te r a ti o n s i n t h e
c e l lu l a r i m m u n esys t e m in a n a c u t e psyc ho log i
c a l s t r e s s s i t ua t i on , am o d e l w i t h a h i g h d
e g r e e o f e x p e r i m e n t a l c o n t ro lwa s c hose n (
20-22) . F i r s t- t im e t a nd e m pa r a c hu t i s t sb e f o
r e , d u r i n g , a n d a f t e r j u m p i n g w e r e c o n t i
n u o u s l ym o n i t o r e d fo r t h e i r h e a r t r at e a n
d p l a s m a c o n c e n -t r at i o n s o f t h e s y m p a t h e
t i c -a d r e n a l h o r m o n e s c o r -t i so l a nd c a t e c
ho la m ine s . A t t h r e e de f ine d t im ep o i n t s l y m p
h o c y t e s a n d t h e i r r e s p e c t iv e s u b s e t swe r
e c ha r a c t e r i z e d f o r c e l l su r f a c e a n t i ge ns
a ndthe i r f unc t i ona l c a pa c i t y .MATERIALS AND M
ETHODSSubjects and Procedure
For ty - f i ve m a le sub j e c t s a ge d 19- 39 ye a r s ( m
e a n= 25 .4 ye a r s ) pa r t i c ipa t e d i n t h i s s t udy a
f t e r g iv ingt h e ir i n f o r m e d c o n s e n t . A l l s u
b j e c t s h a d p a s s e d a nin t e ns ive he a l t h e xa m
ina t ion be f or e e n t r a nc e . Sub-j e c t s w i t h d r u g
o r a l c o h o l a b u s e , m e d i c a t i o n , o ri n f e ct i
o n s w i t h i n t h e l a st 2 w e e k s w e r e e x c l u d e d
.A l l s u b j e c ts p e r f o r m e d t a n d e m j u m p s , i .
e . , t h en o v i c e w a s s e c u r e d i n f ro n t o f a n e x
p e r i e n c e dt a n d e m m a s t e r . J u m p s w e r e p e r
f o r m e d b e t w e e n10 .00 a nd 12 .00 h r . T wo to t h r e e
hour s be f or ej u m p i n g t h e c a t h e t e r w a s i n s e r
te d a n d b a s e li n es a m p l e s w e r e d r a w n . B o a r
d i n g t i m e w a s 3 0 m i nbe f or e e x i t . Dur ing a sc e n
t o f t he p l a ne t o e x i ta l t it ude ( 3500 m ) sub j e c t
s s a t i n t he p l a ne w i thou tbe ing phys i c a l l y a c t i
ve . Jum pe r s ha d 45 se c f r e e- f al lt im e un t i l t he pa
r a c hu te wa s r e l e a se d a nd a ppr ox i -m a t e l y 5 m i
n u n d e r t h e o p e n p a r a c h u t e u n t i l la n d -ing .
Sub je c t s c om ple t e d t he S t a t e T r a i t Anxie tyI nve
n to r y ( ST AI ) ( 23) t o de t e r m ine t he s t a t e a nx i
-e ty a t ba se l i ne a nd im m e dia t e ly be f or e e x i t .
He a r tr a te w a s c o n t i n u o u s l y r e c o r d e d w i t
h A g - A g C I e le c -t r ode s i n t he l e a d I I c onf igur a
t i on by us ing a por t a -b l e r e c o r d i n g s y s t e m (2
4). F o r c o n t i n u o u s b l o o dsa m p l ing a c a the t e r
( Ce r to fix , Br a un M e l sunge n ,M e l sunge n , Ge r m a ny
) wa s i nse r t e d i n to a b r a c h ia l i sv e i n . T h e c a
t h e t e r w a s c o n n e c t e d to h e p a r i n i z e ds i l i
c o n t u b i n g ( 1 m m + ) . B l o o d w a s c o n t i n u o u s
l yd r a w n b y a s m a l l p o r t a b le p u m p ( F r e s e n i
u s , H o m -bur g , G e r m a ny) a nd c o l l e c t e d in l i th
ium he pa r in
t u b e s c o n t a i n in g g l u t a t h i o n e . B l o o d f
lo w w a sa d j u s t e d to 0 . 8 m l / m i n . E v e r y 1 0 m i
n t h e t u b e s w e r ec h a n g e d a n d s a m p l e s f o r t
h e e n d o c r i n e v a ri a b l eswe r e f r a c t iona t e d .
T he s a m p le s we r e c e n t r i f uge d at4 C a n d s t o r e
d f r o z e n a t - 7 0 C u n t il a s s a y e d . I na d d i t i o
n , b l o o d s a m p l e s w e r e d r a w n t o d e t e r m i n
ei m m u n o l o g i c a l p a r a m e t e r s : 2 h r b e f o r e
t h e j u m p( ba se li ne ) , im m e dia t e ly a ft e r , a nd 1
h r a f t e r t hej u m p . A l l a n a l y s e s w e r e p e r f o
r m e d i m m e d i a t e l ya f t e r the l a s t s a m p le wa s
c o l l e c t e d .
Endocrine nalysesAl l sa m ple s o f e a c h sub j e c t we r e
a na ly z e d i n t hes a m e a s s a y . C o r t i s o l w a s d e
t e r m i n e d b y r a d i o im -m u n o a s s a y ( B i e r m a n
n G m b H , B a d N a u h e i m , G e r -m a n y ) . C a t e c h o
l a m i n e p l a s m a l e v el s w e r e a n a l y z e d
b y h i g h - p r e s s u r e l i q u i d c h r o m a t o g r a
p h y ( H P L C ,e l e c t r oc he m ic a l de t e c to r ) .
Monoclonal ntibodiesT h e m o n o c l o n a l a n ti b o d i e s
u s e d h a v e b e e n d e -sc r ibe d i n de t a i l p r e v ious
ly ( 25): CD2 ( L e u5b) , C D3( L e u 4 ) , C D 8 ( L e u 2 a ) ,
C D 1 6 ( L e u l l b ) , C D 5 6( L e u l 9 P E ) , a n d C D 2 5
w e r e p u r c h a s e d f r o m B e c t o nDic k inson ( He ide
lbe r g , Ge r m a ny) . CD3 ( OKT 3) ,C D 4 ( O K T 4 ) , a n d C
D 8 ( O K T 8 ) w e r e f r o m O r t h o( N e c k a r g e m f in d
, G e r m a n y ) . C D 2 R ( T l l . 3 ) , C D 2 6 ,a n d C D 5 6
( N K H - 1 A ) w e r e g e n e r o u s l y p r o v i d e d b yD r
s . S . F . S c h l o s s m a n n , E . L . R e i n h e r z , a n d
J.R i t z ( Da na Fa r be r Ca nc e r I ns t i t u t e , Bos ton ,
M A) .T u27 ( an ti -p75) wa s ge ne r ous ly g ive n by Dr . K .S
u g a m u r a ( D e p a r t m e n t o f M i c r o b i o l o g y , T
o h u k oU n i v e r s i t y S c h o o l o f M e d i c i n e , S e
n d a i , J a p a n ) .
Phenotypic nalysesPhe notyp i c a na lyse s we r e pe r f o r m
e d by i nd i r e c ti m m u n o f l u o r e s e e n c e u s i n g
f l u o re s c e in - c o n j u g a te d
goa t a n t i -m ouse F ( a b ) I g ( GM - FI T C, D ia nova ,
Ha m -burg, Germany) . For two-color ana lyses di rec t ly la -be l
e d a n t i bod ie s we r e u t il iz e d . T he s t a in ing p r
oc e dur ehas b een descr ibed in de ta il previo usly (26) . Brie
f ly , 1to 3 105 ce ll sAvell we re in cubated wi th mu r
inemonoclona l ant ibodies a t an opt imal di lut ion for 30m in .
No nspe c i f ic b ind ing wa s e l im ina te d by m ix ingthe sa m
ple s w i th a 1 :5 so lu t i on o f a c om m e r c i a lhum a n I
gG ( I n tr a g lob in, Biotes t , Fran kfur t , G erma-ny) . Sa m
ple s we r e i nc uba t e d fo r a no the r 30 m in w i thGM - FI T
C a nd w a she d t h r e e t im e s , a nd 10 ,000 c e ll s
J ourna l o f C l in ic a l Imm uno logy Vol . 13 No . 2
1993
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