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).”

“…(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).”

“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 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).”

“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.”

“…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.”

“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…”

“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.”

“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…”

“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).”

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

“…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).”

“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 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).”

“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).”

“…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).”

“, 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.”

“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 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.”

“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.”

“…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).”

“…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).”

“…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).”

“…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).”

“Once they receive word of a threat, they leave their barracks and enter the “boulevards” (i.e., the bloodstream) and migrate to the “battlefield” (i.e., the site of tissue damage or infection), which could be anywhere in the body (Dhabhar et al. 2012).”

“Different stressors may trigger a redistribution of leukocytes from immune reservoirs to the circulation and certain peripheral tissues (Dhabhar et al., 2012).”

“However, the field is still in the process of defining a road map to clarify under what circumstances psychological stress activates “eustress” responses and psychobiological resilience mechanisms, or alternatively, promotes premature aging and morbidity (Dhabhar et al., 2012).”

“However, these studies are confounded by the use of whole blood (95,96) (see discussion of limitations hereinafter) and the cross-sectional study design, which cannot tease apart directionality or causality.”

“, have defined “good” versus “bad” stress in terms of the duration of the biological stress response and its adaptive versus deleterious effects, and have stated that stress does not always have deleterious effects, and in some cases can even have beneficial effects on brain, body, and health [3; 4; 7; 11; 29; 30; 32;…”

“Brief or acute stressors activate sympathetic signaling that increases norepinephrine (NE) to mobilize ‘housed’ leukocytes into circulation from reservoirs including the spleen, BM, and lymph nodes (Dhabhar et al, 2012).”

“Cells were identified as: (1) B cells (CD45 B220CD19CD11b), (2) CD4 T cells (CD45CD3CD90.”

“Immune cells “move to their battle stations” and traffic via the circulation to places in the body where they can fight an infection or heal a wound (Dhabhar et al., 2012).”

“With acute stress, SNS activation is associated with increased egress of leukocytes, especially myeloid cells (e.g., monocytes and granulocytes), from the BM that transiently accumulate in circulation (Engler et al., 2004; Dhabhar et al., 2012).”

“Moreover, peripheral and central IL-1 can initiate neuroendocrine responses that promote activation and redistribution of peripheral myeloid cells (Bierhaus et al., 2003; Sternberg, 2006; Sorrells et al., 2009; Dhabhar et al., 2012).”

“In fact, cell type distribution also varies widely by age (Patin et al., 2018; Rausser et al., 2021), in response to stress (Dhabhar et al., 2012), and across the day-night diurnal cycle (Dhabhar et al., 1994; Lange et al., 2010).”

“[44] Dhabhar FS, MalarkeyWB, Neri E, McEwen BS.”

“Stress-induced catecholamines also play a critical role in leukocyte mobilization and redistribution of leukocytes from primary immune compartments such as spleen and bone marrow [93].”

“It has been well characterized that chronic stress increases the infiltration of monocytes and dendritic cells into the brain (102) and this behavior mediates chronic stress-induced anxiety-like behavior (103), while stress hormones in response to acute and repeated stress orchestrate the redistribution of immune cell…”

“Dhabhar and his colleagues have long suggested that GCs mobilize immune defenses and facilitate immune responding to damage and infection that can occur during fight/flight emergencies (Dhabhar et al., 2012).”

“This oscillatory production of corticosterone is necessary in maintaining the physiological functions (e.g., homeostatic ACTH levels) but not enough to elicit a stress response (Jacobson et al., 1988; Dhabhar et al., 2012).”

“While there is evidence that GCs are important for transient leukocyte redistribution following acute stress (46), data here show a primary role for the SNS in the egress of primed splenic monocytes in sensitized mice.”

“(Dhabhar et al., 2012) The body’s response is like an orchestra involving many players that need to work in harmony!”

“Subsequent research found that a temporary spike in cortisol levels following an induced mild stressor in rats (brief confinement to a small cage) led to a temporary boost in immune response (Dhabhar et al., 2012).”

“window into the system—on their way to the battle stations, the target tissue, such as skin and the gastrointestinal tract (42).”

“They may return to their pre-exercise location, or might migrate to areas/tissues that now require their sentinel and/or reparative action following activation of the biological stress response [17].”

“It is important to note that leukocytes exhibit distinct sensitivities and redistribution kinetics in response to each stress hormone, depending on the type of cell and its functional characteristics (Dhabhar et al., 2012).”

“The initial response in generalized stress, including stroke, is a nonspecific activation of the immune system, where the first-line response is the increase in neutrophil count and a decrease in the lymphocyte count [32,33].”

“For example, stress hormones help reconfigure immune resources to enhance protection against wound infections during fight-or-flight behaviour (Dhabhar et al., 2012; Dhabhar, 2014).”

“…inhibit inflammation (Edwards, 2012); however, numerous studies have shown that acute stress-mediated increases in corticosterone and epinephrine can stimulate leukocyte trafficking and extravasation at the site of injury in an immune cell-specific manner (Dhabhar, 2009; Dhabhar et al., 2012).”

“The generalized stress can lead to nonspecific activation of the immune system, increasing the neutrophil count and decreasing the lymphocyte count [52, 53].”

“The increase in immune components, such as cytokines, causes a further increase in GCs which then acts as negative feedback on the immune system and begins immunosuppression (Dobbs et al. 1996; Dhabhar et al. 2012).”

“Lymphocyte redistribution, which can occur temporarily in response to acute stress (Dhabhar, 2011; Dhabhar et al., 2012; Rosenberger et al., 2009) may lead to ‘‘pseu do-lengthening,” whereby average TL measurements increase due to an increase in cell types having longer telomeres (Epel, 2012).”

“Subsequently, in the hours following exercise, the same e ff ector cells migrate to tissues, leaving blood to search for cells infected with viruses, bacteria, or those that have undergone a malignant transformation [55, 56].”

“Various non-mutually exclusive hypotheses have been suggested as to why stress hormones alter immune function (e.g., Råberg et al. 1998; Dhabhar et al. 2012).”

“In various stressful situations, the physiological response of the immune system is characterized by an increase in neutrophils and a decrease in lymphocytes.(25,26) Neutrophils play an important role in first-line defense during inflammation; once activated, they Table 1 Baseline characteristics of the study particip…”

“The non-specific immune system activation, depicted by an increase in the neutrophil count and a decrease in the lymphocyte count, may be the first line response during generalized stress, leading to an imbalance between neutrophils and lymphocytes in the peripheral circulation [41,42].”

“Thus, acute stress promotes leukocyte mobilization to the blood (Dhabhar et al., 2012) and infiltration into the site of inflammation (Viswanathan and Dhabhar, 2005) and mostly activates proliferative responses of immune cells (Rinner et al.”

“Immune cells constantly traffic between the blood and various lymphoid and non-lymphoid organs and studies in rodents suggest that behavioral stress induces a significant redistribution of T cells in the body (131).”