Stress-induced redistribution of immune cells–from barracks to boulevards to battlefields: a tale of three hormones–Curt Richter Award winner

“…epinephrine (EPI) and corticosterone (CORT), that exert the widespread physiological effects of an acute stress response (Dhabhar and McEwen, 2001; Sapolsky et al., 2000), are also the major endocrine mediators of specific phases and redistribution profiles of psychological and physical…”

“The blood is a critical compartment through which immune cells must pass in order to maintain their normal surveillance pathways and to rapidly reach sites of de novo immune activation (e.g., wounding, sterile tissue damage and inflammation, or antigen or pathogen entry) (Springer, 1994).”

“While stress can be harmful when it is chronic or long lasting (Chrousos and Kino, 2007; Glaser and KiecoltGlaser, 2005; Irwin et al., 1990; McEwen, 1998), it is often overlooked that a stress response has salubrious adaptive effects in the short run (Dhabhar and McEwen, 2007; Dhabhar and…”

“…leukocyte rolling, the first step in the cascade of reactions that leads to leukocyte adhesion and transmigration, critical steps for leukocyte surveillance pathways and leukocyte response to immune activation/inflammation (Butcher and Picker, 1996; Khan et al., 2003; Wedepohl et al., 2011).”

“This procedure approximates stress that is largely psychological in nature due to the perception of confinement on part of the animal (for review see: Berkenbosch et al., 1991; Glavin et al., 1994).”

“Since exercise induces endocrine changes that are similar to stress (Pedersen and Hoffman-Goetz, 2000; Walsh et al., 2011), these findings are also likely to apply to the effects of exercise on immune cell distribution/function.”

“…activates the autonomic nervous system (Kvetnansky et al., 1993), and the hypothalamic-pituitary-adrenal axis (Dhabhar et al., 1993, 1995a, 1994; Plotsky and Meaney, 1993), and results in the activation of adrenal steroid receptors throughout the body (Dhabhar et al., 1995a; Plotsky and Meaney,…”

“We suggest that the brain, which is also a site for immune cell traffic (Gottfried-Blackmore et al., 2009; Miller, 2010; Silver et al., 1996; Ziv et al., 2006), and where immune cells are now thought to play a role in facilitating homeostasis, neurogenesis, and function (Ziv et al., 2006), may also…”

“This model represents significant advances in our understanding of the hormone mediators, source organs, kinetics, direction, leukocyte subpopulation specificity, and target organs, of stress-induced changes in blood immune cell numbers (Dhabhar and McEwen, 1997).”

“…these differences it has been hypothesized that these differential effects are achieved by differences in overall stress hormone sensitivity or receptivity of the immune response being affected, or by differences in the duration of hormone exposure (Dhabhar, 2009b; Dhabhar and McEwen, 2001).”

“For example, CD62L+ Th and CTLs cells are thought to be either naı̈ve or central memory Tcells while CD62L Th and CTLs are thought to be effector T cells (Seder and Ahmed, 2003).”

“Numerous studies have examined the effects of specific stress hormones on blood immune cell numbers (Benschop et al., 1996; Dale et al., 1974; Dhabhar et al., 1995b, 1996; Fauci and Dale, 1974; Schedlowski et al., 1993a).”

“It must be noted that immune system induced activation of the stress axes is generally thought to induce a regulatory loop by which stress hormones prevent immune responses from becoming chronically activated or autoimmune (Butts and Sternberg, 2004; Sternberg et al., 1989; Tonelli et al., 2001).”

“However, it is known that under certain conditions, physiological levels of endogenous glucocorticoids have immunoenhancing effects (Dhabhar and McEwen, 1999) while under other conditions similar hormone levels are immuno-suppressive.”

“, 1984), PE-conjugated W3/25, as a marker for helper T lymphocytes (Brideau et al., 1980), PE-Cy5-conjugated OX-8, as a marker for cytolytic T cells (CTL) (Barclay, 1981; Johnson et al.”

“…(Dhabhar et al., 1993), physical (e.g., exercise (Pedersen and Hoffman-Goetz, 2000)), and physiological (e.g., immune activation) (Dunn, 1993; Elenkov et al., 2005; Kusnecov and Goldfarb, 2005; Silverman et al., 2005; Sternberg et al., 1989) stressors (Kvetnansky et al., 1998; Pacak et al., 1998).”

“…inflammatory/classical (CD62L+) monocytes (Gordon and Taylor, 2005; Tacke and Randolph, 2006) show mobilization and trafficking, while resident/non-classical (CD62L ) monocytes (Gordon and Taylor, 2005; Tacke and Randolph, 2006) that are present in the blood traffic out to tissues during stress.”

“Numerous studies have examined the effects of specific stress hormones on blood immune cell numbers (Benschop et al., 1996; Dale et al., 1974; Dhabhar et al., 1995b, 1996; Fauci and Dale, 1974; Schedlowski et al., 1993a).”

“The fact that inflammation can activate the stress axis (Dunn, 1993; Elenkov et al., 2005; Kusnecov and Goldfarb, 2005; Silverman et al., 2005; Sternberg et al., 1989) implies that under certain conditions, an immune response may also tap into the stress leukocyte redistribution cascade to deliver more leukocytes to t…”

“…(Dhabhar et al., 1993), physical (e.g., exercise (Pedersen and Hoffman-Goetz, 2000)), and physiological (e.g., immune activation) (Dunn, 1993; Elenkov et al., 2005; Kusnecov and Goldfarb, 2005; Silverman et al., 2005; Sternberg et al., 1989) stressors (Kvetnansky et al., 1998; Pacak et al., 1998).”

“Numerous studies have examined the effects of specific stress hormones on blood immune cell numbers (Benschop et al., 1996; Dale et al., 1974; Dhabhar et al., 1995b, 1996; Fauci and Dale, 1974; Schedlowski et al., 1993a).”

“In contrast, a short-term decrease in blood leukocyte numbers represents a trafficking of cells out of the blood to target organs such as the skin (Dhabhar and McEwen, 1996) and lung (Kradin et al., 2001), or sites of immune activation (Dhabhar and McEwen, 1997; Dhabhar and Viswanathan, 2005;…”

“Regulated redistribution of immune cells among different body compartments is essential for effective immune surveillance and salubrious immune function (Butcher, 1990; Sprent and Tough, 1994).”

“The effects of stress and stress hormones on the direction and magnitude of distribution of dendritic cells (Rossi and Young, 2005), and gammadelta T cells (Scotet et al., 2008), which are also critical for effective immune function, need to be carefully examined.”

“Corticosterone replacement normalizes basal levels of adrenocorticotropic hormone (ACTH), blood leukocyte numbers, and catecholamine hormones (Kvetnansky et al., 1993), all of which are abnormally high in ADX animals.”

“We suggest that the brain, which is also a site for immune cell traffic (Gottfried-Blackmore et al., 2009; Miller, 2010; Silver et al., 1996; Ziv et al., 2006), and where immune cells are now thought to play a role in facilitating homeostasis, neurogenesis, and function (Ziv et al., 2006), may also…”

“Briefly, lymphocyte subsets were defined using 3-color panels consisting of the following monoclonal antibodies (Harlan, Indianapolis, IN): In the first panel we used FITC-conjugated OX-19 as a pan-T cell marker (Dallman et al., 1984), PE-conjugated W3/25, as a marker for helper T lymphocytes (Brideau et al.”

“…al., 2003; Brosschot et al., 1994; Dhabhar et al., 1995b; Mills et al., 1995; Schedlowski et al., 1993b; Stefanski and Grùner, 2006), and exercise (Goebel and Mills, 2000; Hong et al., 2004; Nagatomi et al., 2000; Okutsu et al., 2008; Pedersen and HoffmanGoetz, 2000) on selected leukocyte…”

“Numerous studies have examined the effects of specific stress hormones on blood immune cell numbers (Benschop et al., 1996; Dale et al., 1974; Dhabhar et al., 1995b, 1996; Fauci and Dale, 1974; Schedlowski et al., 1993a).”

“Restraint activates the autonomic nervous system (Kvetnansky et al., 1993), and the hypothalamic-pituitary-adrenal axis (Dhabhar et al., 1993, 1995a, 1994; Plotsky and Meaney, 1993), and results in the activation of adrenal steroid receptors throughout the body (Dhabhar et al., 1995a; Plotsky and…”

“Thus, different types of stressors (e.g., cold stress vs. immobilization vs. inflammatory pain vs. hypoglycemia), that are known to induce different relative increases in circulating concentrations of NE, EPI, and CORT (Kvetnansky et al., 1998; Pacak et al., 1998), are likely to have different effects on the kinetics…”

“While stress can be harmful when it is chronic or long lasting (Chrousos and Kino, 2007; Glaser and KiecoltGlaser, 2005; Irwin et al., 1990; McEwen, 1998), it is often overlooked that a stress response has salubrious adaptive effects in the short run (Dhabhar and McEwen, 2007; Dhabhar and…”

“In a second panel, we used FITC-conjugated anti-CD62L antibody to identify L-selectin, PE-conjugated OX33, to identify B cells (Woollett et al., 1985), and PECy5-conjugated OX-8 to identify CTLs. Antibody isotype controls were used to set the negative criterion analysis.”

“Restraint activates the autonomic nervous system (Kvetnansky et al., 1993), and the hypothalamic-pituitary-adrenal axis (Dhabhar et al., 1993, 1995a, 1994; Plotsky and Meaney, 1993), and results in the activation of adrenal steroid receptors throughout the body (Dhabhar et al., 1995a; Plotsky and…”

“…replacement (via pellets or osmotic pumps), drinking water corticosterone also facilitates the normal termination of a stress-induced ACTH response (Akana et al., 1988; Jacobson et al., 1988), and simulates the circadian corticosterone rhythm as animals drink at the beginning of the active period.”

“While this hypothesis needs to be tested through further experiments, studies have shown important temporal differences in the sensitivity of immune reactions to the enhancing or suppressive effects of physiologic concentrations of stress hormones (Wiegers et al., 1995; Wiegers and Reul, 1998).”

“However, studies have shown that stressinduced leukocyte mobilization is also observed in splenectomized subjects (Baum et al., 1996; Schedlowski et al., 1996).”

“As a result, this redistribution response enhances immune function in compartments that are enriched with immune cells during/following stress (Dhabhar, 2009b; Dhabhar and McEwen, 1996; Dhabhar et al., 2010; Viswanathan et al., 2005; Viswanathan and Dhabhar, 2005).”

“Moreover, the functional consequences of these effects of chronic stress are indicated by a significant suppression of skin immunity (Dhabhar and McEwen, 1997; Dhabhar et al., in press; Saul et al., 2005).”

“We suggest that the brain, which is also a site for immune cell traffic (Gottfried-Blackmore et al., 2009; Miller, 2010; Silver et al., 1996; Ziv et al., 2006), and where immune cells are now thought to play a role in facilitating homeostasis, neurogenesis, and function (Ziv et al., 2006), may also…”

“Numerous studies have examined the effects of specific stress hormones on blood immune cell numbers (Benschop et al., 1996; Dale et al., 1974; Dhabhar et al., 1995b, 1996; Fauci and Dale, 1974; Schedlowski et al., 1993a).”

“Part of this mobilization may occur through catecholaminedriven splenic capsule contraction and subsequent extrusion of erythrocytes and leukocytes into the blood (Stewart and McKenzie, 2002).”

“, 2003), effector-memory CTLs (Campbell et al., 2009), and tissuedirected memory-type gamma-delta T cells (Anane et al.”

“Regulated redistribution of immune cells among different body compartments is essential for effective immune surveillance and salubrious immune function (Butcher, 1990; Sprent and Tough, 1994).”

“…these differences it has been hypothesized that these differential effects are achieved by differences in overall stress hormone sensitivity or receptivity of the immune response being affected, or by differences in the duration of hormone exposure (Dhabhar, 2009b; Dhabhar and McEwen, 2001).”

“, 2005), rats (Dhabhar and McEwen, 1996, 1999), hamsters (Bilbo et al., 2002), and human subjects (Edwards et al.”

“Moreover, there are significant inter-individual differences in the effects of stress (Hellhammer and Wade, 1993; Marsland et al., 2002), especially in case of unrecognized and unintended stressors that are also uncontrolled.”

“This redistribution is similar across many species, including humans, which suggests that it is evolutionarily significant and likely to confer an adaptive advantage (Dhabhar, 1998, 2009a,b).”

“Numerous studies have examined the effects of stress on leukocyte-endothelial cell adhesion molecule expression on circulating immune cells (Bauer et al., 2001; Goebel and Mills, 2000; Hong et al., 2004; Mills et al., 2003; Okutsu et al., 2008; Rainer et al., 1999; Redwine et al., 2003; Shephard, 2003).”

“Such enhancement has been observed in mice (Dhabhar et al., 2000, 2010; Dhabhar and Viswanathan, 2005; Saint-Mezard et al., 2003; Viswanathan et al., 2005), rats (Dhabhar and McEwen, 1996, 1999), hamsters (Bilbo et al., 2002), and human subjects (Edwards et al., 2007; Rosenberger et al., 2009) (for…”

“Numerous studies have examined the effects of specific stress hormones on blood immune cell numbers (Benschop et al., 1996; Dale et al., 1974; Dhabhar et al., 1995b, 1996; Fauci and Dale, 1974; Schedlowski et al., 1993a).”

“In seemingly contradicting results, acute stress has been shown to suppress splenic IgM production (Zalcman and Anisman, 1993), and splenic and peripheral blood responses to T cell mitogens (Cunnick et al., 1990).”

“Such enhancement has been observed in mice (Dhabhar et al., 2000, 2010; Dhabhar and Viswanathan, 2005; Saint-Mezard et al., 2003; Viswanathan et al., 2005), rats (Dhabhar and McEwen, 1996, 1999), hamsters (Bilbo et al., 2002), and human subjects (Edwards et al., 2007; Rosenberger et al., 2009) (for…”

“However, it is of interest to note that an acute stressor experienced during immunization enhances dendritic cell maturation and trafficking to lymph nodes (Viswanathan et al., 2005).”

“Although the functional and clinical ramifications of stress-induced leukocyte redistribution have yet to be fully appreciated and harnessed, numerous studies have elegantly examined the effects of stress (Bosch et al., 2003; Brosschot et al., 1994; Dhabhar et al., 1995b; Mills et al., 1995; Schedlowski et al., 1993b;…”

“For example, it has been shown that acute stress induces a redistribution of leukocytes from the blood to the skin and that this redistribution is accompanied by a significant enhancement of skin cell mediated immunity (Dhabhar and McEwen, 1996; Dhabhar et al., 2010; Dhabhar and Viswanathan, 2005).”

“8) that is based on the findings described here and those in the literature (Baum et al., 1996; Benschop et al., 1996; Dhabhar, 2009b; Dhabhar and McEwen, 1996, 1997; Engler et al., 2004).”

“Other studies have shown that T cell subtypes that are more likely to traffic to sites of inflammation (Bosch et al., 2003), effector-memory CTLs (Campbell et al.”

“Numerous studies have shown that stress can significantly affect immune cell distribution and function (for review see: Butts and Sternberg, 2008; Chrousos, 2010; Dhabhar, 2009b; Dhabhar and McEwen, 1997; Glaser and Kiecolt-Glaser, 2005).”

“Numerous studies have examined the effects of specific stress hormones on blood immune cell numbers (Benschop et al., 1996; Dale et al., 1974; Dhabhar et al., 1995b, 1996; Fauci and Dale, 1974; Schedlowski et al., 1993a).”

“Numerous studies have shown that stress can significantly affect immune cell distribution and function (for review see: Butts and Sternberg, 2008; Chrousos, 2010; Dhabhar, 2009b; Dhabhar and McEwen, 1997; Glaser and Kiecolt-Glaser, 2005).”

“While this hypothesis needs to be tested through further experiments, studies have shown important temporal differences in the sensitivity of immune reactions to the enhancing or suppressive effects of physiologic concentrations of stress hormones (Wiegers et al., 1995; Wiegers and Reul, 1998).”

“…and function through specific subtypes of alphaand beta-adrenergic receptors have been discussed in excellent reviews (Benschop et al., 1996; Kavelaars, 2002; Kohm and Sanders, 2000; Sanders, 2006) and the catecholaminerelated results presented here are in agreement with elegant studies by…”

“…and harnessed, numerous studies have elegantly examined the effects of stress (Bosch et al., 2003; Brosschot et al., 1994; Dhabhar et al., 1995b; Mills et al., 1995; Schedlowski et al., 1993b; Stefanski and Grùner, 2006), and exercise (Goebel and Mills, 2000; Hong et al., 2004; Nagatomi et al.,…”

“Other studies have suggested that glucocorticoid hormones suppress neutrophil CD62L mRNA expression and that this induces a decrease in cell-surface protein expression of CD62L that is correlated with a glucocorticoid-induced neutrophilia (Weber et al., 2001).”

“Additionally, Redwine et al. (2003) have shown that acute stress increases PBMC chemotaxis and adhesion molecule (Mac-1) expression in human subjects (Redwine et al., 2003).”

“Moreover, there are significant inter-individual differences in the effects of stress (Hellhammer and Wade, 1993; Marsland et al., 2002), especially in case of unrecognized and unintended stressors that are also uncontrolled.”

“, 1993b; Stefanski and Grùner, 2006), and exercise (Goebel and Mills, 2000; Hong et al., 2004; Nagatomi et al., 2000; Okutsu et al., 2008; Pedersen and HoffmanGoetz, 2000) on selected leukocyte subpopulations.”

“This procedure approximates stress that is largely psychological in nature due to the perception of confinement on part of the animal (for review see: Berkenbosch et al., 1991; Glavin et al., 1994).”

“have shown that a short stressor (1 min handling) induced an increase in mitogen-induced proliferation of T and B cells obtained from peripheral blood, while a longer stressor (2 h immobilization) induced a decrease in the same proliferative responses (Rinner et al., 1992).”

“The injected hormone concentrations were based on amounts used in other studies (Kradin et al., 2001; Meng et al., 1996; van Gool et al., 1984), and determined to induce circulating concentrations and effects that were within the range of a physiological stress response.”

“…and Viswanathan, 2005; Saint-Mezard et al., 2003; Viswanathan et al., 2005), rats (Dhabhar and McEwen, 1996, 1999), hamsters (Bilbo et al., 2002), and human subjects (Edwards et al., 2007; Rosenberger et al., 2009) (for review see: Dhabhar, 2009b; Dhabhar and McEwen, 2007; Edwards et al., 2007).”

“There is also the important possibility that some early and late effects of glucocorticoids on immune cells may be mediated through faster-acting non-classical/alternative signaling pathways (for review see: Orchinik, 1998; Song and Buttgereit, 2006).”

“Such non-genomic pathways of glucocorticoid signaling have also been reported in immune cells (Boldizsar et al., 2010) and are likely to mediate some of the effects of stress and stress steroids on immune cell distribution and function.”

“…1997; Dhabhar et al., 1995b, 1996; Fauci, 1975; Kradin et al., 2001) and human subjects studies (Altemus et al., 2001; Atanackovic et al., 2004; Fauci and Dale, 1974; Rosenberger et al., 2009; Schedlowski et al., 1993b), suggesting that the effects described here are representative and robust.”

“…leukocyte rolling, the first step in the cascade of reactions that leads to leukocyte adhesion and transmigration, critical steps for leukocyte surveillance pathways and leukocyte response to immune activation/inflammation (Butcher and Picker, 1996; Khan et al., 2003; Wedepohl et al., 2011).”

“…and Viswanathan, 2005; Saint-Mezard et al., 2003; Viswanathan et al., 2005), rats (Dhabhar and McEwen, 1996, 1999), hamsters (Bilbo et al., 2002), and human subjects (Edwards et al., 2007; Rosenberger et al., 2009) (for review see: Dhabhar, 2009b; Dhabhar and McEwen, 2007; Edwards et al., 2007).”

“…Indianapolis, IN): In the first panel we used FITC-conjugated OX-19 as a pan-T cell marker (Dallman et al., 1984), PE-conjugated W3/25, as a marker for helper T lymphocytes (Brideau et al., 1980), PE-Cy5-conjugated OX-8, as a marker for cytolytic T cells (CTL) (Barclay, 1981; Johnson et al., 1985).”

“The injected hormone concentrations were based on amounts used in other studies (Kradin et al., 2001; Meng et al., 1996; van Gool et al., 1984), and determined to induce circulating concentrations and effects that were within the range of a physiological stress response.”

“In addition to these changes in leukocyte distribution, acute stress and stress hormones have also been shown to enhance immune cell function (Dhabhar and McEwen, 1996, 1999; Dhabhar et al., 2010; Dhabhar and Viswanathan, 2005; Viswanathan et al., 2005; Wiegers et al., 1993, 1994).”

“, 2001), or sites of immune activation (Dhabhar and McEwen, 1997; Dhabhar and Viswanathan, 2005; Viswanathan and Dhabhar, 2005), or back to source compartments from which the cells were initially mobilized (Dhabhar, 1998; Stefanski, 2003).”

“However, studies have shown that stressinduced leukocyte mobilization is also observed in splenectomized subjects (Baum et al., 1996; Schedlowski et al., 1996).”

“In addition to these changes in leukocyte distribution, acute stress and stress hormones have also been shown to enhance immune cell function (Dhabhar and McEwen, 1996, 1999; Dhabhar et al., 2010; Dhabhar and Viswanathan, 2005; Viswanathan et al., 2005; Wiegers et al., 1993, 1994).”

“This was necessary for restoring permissive functions of corticosterone that are lost following ADX (Ambrose, 1964; De Kloet, 1995; Ingle, 1936, 1954).”

“…of alphaand beta-adrenergic receptors have been discussed in excellent reviews (Benschop et al., 1996; Kavelaars, 2002; Kohm and Sanders, 2000; Sanders, 2006) and the catecholaminerelated results presented here are in agreement with elegant studies by Engler et al. who used catecholamine…”

“The fact that inflammation can activate the stress axis (Dunn, 1993; Elenkov et al., 2005; Kusnecov and Goldfarb, 2005; Silverman et al., 2005; Sternberg et al., 1989) implies that under certain conditions, an immune response may also tap into the stress leukocyte redistribution cascade to deliver more leukocytes to t…”

“Numerous studies have examined the effects of stress on leukocyte-endothelial cell adhesion molecule expression on circulating immune cells (Bauer et al., 2001; Goebel and Mills, 2000; Hong et al., 2004; Mills et al., 2003; Okutsu et al., 2008; Rainer et al., 1999; Redwine et al., 2003; Shephard, 2003).”

“This was necessary for restoring permissive functions of corticosterone that are lost following ADX (Ambrose, 1964; De Kloet, 1995; Ingle, 1936, 1954).”

“…through specific subtypes of alphaand beta-adrenergic receptors have been discussed in excellent reviews (Benschop et al., 1996; Kavelaars, 2002; Kohm and Sanders, 2000; Sanders, 2006) and the catecholaminerelated results presented here are in agreement with elegant studies by Engler et al. who…”

“Numerous studies have examined the effects of stress on leukocyte-endothelial cell adhesion molecule expression on circulating immune cells (Bauer et al., 2001; Goebel and Mills, 2000; Hong et al., 2004; Mills et al., 2003; Okutsu et al., 2008; Rainer et al., 1999; Redwine et al., 2003; Shephard, 2003).”

“It must be noted that immune system induced activation of the stress axes is generally thought to induce a regulatory loop by which stress hormones prevent immune responses from becoming chronically activated or autoimmune (Butts and Sternberg, 2004; Sternberg et al., 1989; Tonelli et al., 2001).”

“In seemingly contradicting results, acute stress has been shown to suppress splenic IgM production (Zalcman and Anisman, 1993), and splenic and peripheral blood responses to T cell mitogens (Cunnick et al.”

“Restraint activates the autonomic nervous system (Kvetnansky et al., 1993), and the hypothalamic-pituitary-adrenal axis (Dhabhar et al., 1993, 1995a, 1994; Plotsky and Meaney, 1993), and results in the activation of adrenal steroid receptors throughout the body (Dhabhar et al., 1995a; Plotsky and…”

“It must be noted that immune system induced activation of the stress axes is generally thought to induce a regulatory loop by which stress hormones prevent immune responses from becoming chronically activated or autoimmune (Butts and Sternberg, 2004; Sternberg et al., 1989; Tonelli et al., 2001).”

“However, studies have shown that stressinduced leukocyte mobilization is also observed in splenectomized subjects (Baum et al., 1996; Schedlowski et al., 1996).”

“…Indianapolis, IN): In the first panel we used FITC-conjugated OX-19 as a pan-T cell marker (Dallman et al., 1984), PE-conjugated W3/25, as a marker for helper T lymphocytes (Brideau et al., 1980), PE-Cy5-conjugated OX-8, as a marker for cytolytic T cells (CTL) (Barclay, 1981; Johnson et al., 1985).”