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Acute Stress Evokes Selective Mobilization of T Cells That Differ in Chemokine Receptor Expression

CITATION:  Bosch, J.A., Berntson, G.G., Cacioppo, J.T., Dhabhar, F.S., & Marucha, P.T. (2003).  Acute stress evokes selective mobilization of T cells that differ in chemokine receptor expression:  A potential pathway linking immunologic reactivity to cardiovascular disease.  Brain, Behavior, and Immunity 17, 251-259.

ABSTRACT:  T lymphocytes and monocytes/macrophages are the most abundant cells found in the atherosclerotic plaque. These cells can migrate towards the activated endothelium through the local release of chemotactic cytokines,or chemokines. Given the important role of leukocyte migration in atherosclerosis and the role of stress in mediating leukocyte trafficking,the present study examined the effects of an acute stressor on the redistribution of T cells (CD3+) and monocytes that express the chemokine receptors CCR5,CCR6,CXCR1,CXCR2,CXCR3, and CXCR4. Forty-four undergraduate students underwent a public speaking task. The acute stressor induced sympathetic cardiac activation, parasympathetic cardiac withdrawal,lymphocytosis,and monocytosis (all p < :001). Although the total number of T lymphocytes did not change,there was a selective increase in the number of circulating T cells expressing CXCR2, CXCR3,and CCR5. The ligands of these receptors are chemokines known to be secreted by activated endothelial cells. Analyses of individual differences in stress-induced responses demonstrated a positive relationship between sympathetic cardiac reactivity and mobilization of the various T cell subsets (:35 < r < :56; p < :05). For the monocytes,all subpopulations increased in parallel with total monocyte numbers,with no relation to changes in sympathetic cardiac drive. These results indicate that acute stress induces a mobilization of T cells that are primed to respond to inflamed endothelium. Acute stressors may thus promote the recruitment of circulating immune cells into the sub-endothelia,and therefore accelerate atherosclerotic plaque formation and potentially contribute to the complications that follow acute stressful events. This mechanism may help explain the link between ress,reactivity, and cardiovascular disease.


Benschop,R. J.,Geenen,R.,Mills, P. J.,Naliboff,B. D., Kiecolt-Glaser, J. K., Herbert,T. B.,van der Pompe,G., Miller,G. E.,Matthews,K. A.,Godaert, G. L., Gilmore, S. L.,Glaser, R.,Heijnen, C. J.,Dopp, J. M.,Bijlsma, J. W., Solomon,G. F.,& Cacioppo,J. T. (1998). Cardiovascular and immune responses to acute psychological stress in young and old women: A meta-analysis. Psychosom. Med., 60(3),290–296.

Benschop,R. J.,Rodriguez-F euerhahn, M.,& Schedlowski,M. (1996). Catecholamine-induced leukocytosis: early observations, current research,and future directions. Brain Behav. Immun., 10(2),77–91.

Berntson,G. G.,Bigger,J. T.,Jr., ,Eckberg, D. L.,Grossman, P.,Kaufm ann,P. G.,Malik,M.,Nagara ja,H. N.,Porges, S. W.,Saul,J. P.,Stone,P. H.,& van der Molen,M. W. (1997). Heart rate variability: Origins,methods ,and interpretive caveats. Psychophysiology, 34(6),623–648 .

Berntson,G. G.,Caciop po,J. T.,& Quigley,K. S. (1993). Cardiac psychophysiology and autonomic space in humans: Empirical perspectives and conceptual implications. Psychol. Bull., 114(2),296–322 .

Berntson,G. G.,Quigley, K. S., Jang, J. F.,& Boysen, S. T. (1990). An approach to artifact identification: Application to heart period data. Psychophysiology, 27(5),586–598.

Bleul,C. C.,Farzan, M.,Choe,H., Parolin,C.,Clark-Le wis,I., Sodroski,J., & Springer,T. A. (1996). The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature, 382(6594),829–833.

Burke-Gaffney,A.,Brooks,A. V. S.,& Bogle,R. G. (2002). Regulation of chemokine expression in atherosclerosis. Vasc. Phamacol., 38,283–292.

Cacioppo,J. T. (1994). Social neuroscience: Autonomic, neuroendocrine,and immune responses to stress. Psychophysiology, 31(2),113–128.

Cacioppo,J. T.,Berntson ,G. G.,Malarke y,W. B.,Kiecolt-Glaser,J. K.,Sheridan, J. F., Poehlmann, K. M.,Burleson, M. H.,Ernst, J. M.,Hawkley, L. C.,& Glaser, R. (1998). Autonomic,neuroend ocrine,and immune responses to psychological stress: The reactivity hypothesis. Ann. N. Y. Acad. Sci., 840,664–673.

Cacioppo,J. T.,Malarkey, W. B.,Kiecolt-Gla ser,J. K., Uchino,B. N.,Sgoutas-E mch,S. A.,Sheridan,J. F., Berntson,G. G., & Glaser,R. (1995). Heterogeneity in neuroendocrine and immune responses to brief psychological stressors as a function of autonomic cardiac activation. Psychosom. Med., 57(2),154–164.

Campbell,J. J.,Haraldsen,G.,Pan,J., Rottman,J.,Qin,S., Ponath,P.,Andrew,D. P.,Warnke,R.,Ruffing,N., Kassam,N.,Wu,L.,& Butcher,E. C. (1999). The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells. Nature, 400(6746),776–780.

Campbell, J. J.,Murphy, K. E., Kunkel,E. J.,Brightling, C. E., Soler,D., Shen,Z.,Boisvert,J.,Greenberg,H. B.,Vierra, M. A.,Goodman ,S. B.,Genovese,M. C.,Wardlaw, A. J., Butcher,E. C., & Wu,L. (2001a). CCR7 expression and memory T cell diversity in humans. J. Immunol., 166(2), 877–884.

Campbell,J. J., Qin, S., Unutmaz,D., Soler,D., Murphy,K. E.,Hodge, M. R.,Wu,L.,& Butcher, E. C. (2001b). Unique subpopulations of CD56+ NK and NK-T peripheral blood lymphocytes identified by chemokine receptor expression repertoire. J. Immunol., 166(11),6477–6482.

Chuntharapai,A.,Lee, J.,Hebert, C. A.,& Kim, K. J. (1994). Monoclonal antibodies detect different distribution patterns of IL-8 receptor A and IL-8 receptor B on human peripheral blood leukocytes. J. Immunol., 153(12),5682–56 88.

Cohen,S.,Hamrick ,N., Rodriguez, M. S.,Feldman, P. J., Rabin,B. S.,& Manuck, S. B. (2002). Reactivity and vulnerability to stress-associated risk for upper respiratory illness. Psychosom. Med., 64(2),302–310.

de Geus,E. J. C.,Willemsen, G. H.,Klaver, C. H.,& van Doornen,L. J. (1995). Ambulatory measurement of respiratory sinus arrhythmia and respiration rate. Biol. Psychol., 41(3),205–227.

de Geus,E. J. C., & van Doornen,L. J. P. (1996). Ambulatory assessment of parasympathetic/sympathetic balance by impedance cardiography. In J. Fahrenberg,& M. Myrtek (Eds.), Ambulatory assessment: Computerassisted psychological and psychophysiological methods in monitoring and filed studies (pp. 141–163). Seattle: Hogrefe and Huber.

Dhabhar,F. S., & McEwen, B. S. (1997). Acute stress enhances while chronic stress suppresses cell-mediated immunity in vivo: a potential role for leukocyte trafficking. Brain Behav. Immun., 11(4),286–306 

Dhabhar,F. S., & McEwen, B. S. (1999). Enhancing versus suppressive effects of stress hormones on skin immune function. Proc. Natl. Acad. Sci. USA, 96(3),1059–1064.

Dhabhar,F. S.,Miller,A. H., Stein,M., McEwen,B. S., & Spencer,R. L. (1994). Diurnal and acute tress-induced changes in distribution of peripheral blood leukocyte subpopulations. Brain Behav. Immun., 8(1),66–79.

Kop,W. J. (1999). Chronic and acute psychological risk factors for clinical manifestations of coronary artery disease. Psychosom. Med., 61(4),476–487.

Kotani,A.,Hori,T.,Matsumura, Y.,& Uchiyama,T. (2002). Signaling of gp34 (OX40 ligand) induces vascular endothelial cells to produce a CC chemokine RANTES/CCL5. Immunol. Lett., 84(1),1.

Krantz,D. S.,Kop, W. J.,Santiag ,H. T.,& Gottdiener, J. S. (1996). Mental stress as a trigger of myocardial ischemia and infarction. Cardiol. Clin., 14(2),271–287.

Kunkel,E. J.,Boisvert,J.,Murph y,K.,Vierra,M. A., Genovese,M. C.,Wardlaw,A. J., Greenberg, H. B., Hodge,M. R.,Wu, L., Butcher, E. C.,& Campbell,J. J. (2002). Expression of the chemokine receptors CCR4, CCR5,and CXCR3 by human tissue-infiltrating lymphocytes. Am. J. Pathol., 160(1),347–355 .

Larson,M. R.,Ader, R.,& Moynihan, J. A. (2001). Heart rate, neuroendocrine,and immunological reactivity in response to an acute laboratory stressor. Psychosom. Med., 63(3), 493–501.

Libby,P.,Ridker,P. M., & Maseri, A. (2002). Inflammation and atherosclerosis. Circulation, 05(9),1135–1143.  258 J.A. Bosch et al. / Brain, Behavior, and Immunity 17 (2003) 251–259

Mach,F., Sauty, A., Iarossi,A. S., Sukhova,G. K., Neote,K., Libby,P., & Luster,A. D. (1999). Differential expression of three T lymphocyte-activating CXC chemokines by human atheroma-associated cells. J. Clin. Invest., 104(8),1041–1050.

Mills,P. J.,Goebel ,M.,Rehman, J.,Irwin, M. R.,& Maisel, A. S. (2000). Leukocyte adhesion molecule expression and T cell naive/memory status following isoproterenol infusion. J. Neuroimmunol., 102(2),137–144.

Oberlin,E.,Amara,A.,Bachelerie,F.,Bessia, C.,Virelizier, J. L.,Arenzana- Seisdedos, F., Schwartz,O.,Heard,J. M., Clark-Lewis,I.,Legler,D. F.,Loetsch er,M., Baggiolini, M.,& Moser,B. (1996). The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cellline-adapted HIV-1. Nature, 82(6594),833–835.

Oppenheim,J. J., Zachariae, C. O., & Goetzl,E. (2000). The role of chemotactic factors and neuropeptides in host defense. Online Cytokine Textbook. San Diego: Academic Press.

Porges,S. W.,& Bohrer, R. E. (1990). The analysis of periodic processes in psychophysiological research. In J. T. Cacioppo, & L. G. Tassinary (Eds.), Principles of psychophysiology: Physical, social, and inferential elements (pp. 708–753).  Cambridge: Cambridge University Press.

Qi,J.,& Kreutzer,D. L. (1995). Fibrin activation of vascular endothelial cells. Induction of IL-8 expression. J. Immunol., 155(2),867–876 .

Qin,S., Rottman,J. B.,Myers, P.,Kassam,N., Weinblatt, M., Loetscher,M.,Koch, A. E.,Moser,B., & Mackay, C. R. (1998). The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J. Clin. Invest., 101(4),746–754.

Reape,T. J.,& Groot,P. H. (1999). Chemokines and atherosclerosis. Atherosclerosis, 147(2),213–225.

Redwine,L.,Snow,S.,Mills,P. J.,& Irwin,M. R. (in press). Acute psychological stress: Effects on chemotaxis and cellular adhesion molecule expression. Psychosom. Med.. Ross,R. (1999). Atherosclerosis—an inflammatory disease. N. Engl. J. Med., 340(2),115–126 .

Rozanski,A.,Blumenthal,J. A.,& Kaplan,J. (1999). Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation, 99(16), 2192–2217.

Saab,P. G.,Matthew s,K. A.,Stoney,C. M.,& McDonald,R. H. (1989). Premenopausal and postmenopausal women differ in their cardiovascular and neuroendocrine responses to behavioral stressors. Psychophysiology, 26(3),270–280.

Sanders,V. M.,& Straub, R. H. (2002). Norepinephrine, the badrenergic receptor,and immunity. Brain Behav. Immun., 16(4),290–332.

Seeger, F. H., Blessing,E.,Gu, L.,Bornhold,R., Denger,S.,& Kreuzer,J. (2002). Fibrinogen induces hemotactic activity in endothelial cells. Acta Physiol. Scand., 176(2),109–115 .

Sgoutas-Emch,S. A.,Cacioppo, J. T.,Uchino,B. N., Malarkey, W.,Pearl, D.,Kiecolt-Gla ser, J. K., & Glaser,R.  (1994). The effects of an acute psychological stressor on cardiovascular,endocrine ,and cellular immune response: a prospective study of individuals high and low in heart rate reactivity. Psychophysiology, 31(3),264–271 .

Sheps,D. S., McMahon,R. P., Becker,L., Carney,R. M., Freedland,K. E.,Cohen,J. D., Sheffield,D., Goldberg,A. D.,Ketterer,M. W.,Pepine,C. J.,Raczynski,J. M.,Light, K.,Krantz,D. S.,Stone,P. H.,Knatterud, G. L.,& Kaufmann,P. G. (2002). Mental stress-induced ischemia and all-cause mortality in patients with coronary artery disease: Results from the Psychophysiological Investigations of Myocardial Ischemia study. Circulation, 105(15),1780–1784.

Sherwood,A.,Allen,M. T.,Fahrenbe rg,J., Kelsey,R. M., Lovallo,W. R.,& van Doornen, L. J. (1990). Methodological guidelines for impedance cardiography. Psychophysiology, 27(1),1–23.

Shin,W. S.,Szuba,A.,& Rockson,S. G. (2002). The role of chemokines in human cardiovascular pathology: enhanced biological insights. Atherosclerosis, 160(1),91–102. 

Song,L., Leung,C., & Schindler, C. (2001). Lymphocytes are important in early atherosclerosis. J. Clin. Invest., 108(2), 251–259.

Uchino,B. N., Cacioppo, J. T.,Malarkey, W., & Glaser, R. (1995). Individual differences in cardiac sympathetic control predict endocrine and immune responses to acute psychological stress. J. Pers. Soc. Psychol., 69(4),736–743.

van Eck,M. M.,Nicolson ,N. A.,Berkhof ,H.,& Sulon, J. (1996). Individual differences in cortisol responses to a laboratory speech task and their relationship to responses to stressful daily events. Biol. Psychol., 43(1),69–84.

Wang, J. M.,Su, S.,Gong,W.,& Oppenheim, J. J. (1998). Chemokines,receptors,and their role in cardiovascular pathology. Int. J. Clin. Lab. Res., 28(2),83–90.

Willemsen,G. H., De Geus, E. J., Klaver, C. H.,Van Doornen, L. J.,& Carroll,D. (1996). Ambulatory monitoring of the impedance cardiogram. Psychophysiology, 33(2),184–193. J.A. Bosch et al. / Brain, Behavior, and Immunity 17 (2003) 251–259 259