Leukocyte adhesion molecule expression and T cell naı̈ve/memory status following isoproterenol infusion
Introduction
Leukocyte redistribution in response to acute sympathetic activation is a well-documented phenomenon (Benschop et al., 1996, for review). Early studies intending to reveal underlying mechanisms focused primarily on catecholamines and leukocyte adrenergic receptor expression. The discovery of the role of cell adhesion molecules in leukocyte trafficking and migration (Springer, 1990; Bevilacqua, 1993; for review) has enabled further significant insight into these mechanisms. Kurokawa et al. (1995), for example, reported that the expression of the membrane glycoprotein L-selectin (CD62L) was associated with a differential mobilization of T cells following intensive exercise; CD62L−, but not CD62L+, T cells were found to be preferentially increased in circulation as a result of exercise. Subsequent studies have confirmed and extended these findings (Jordon et al., 1997; Miles et al., 1998; Mills et al., 1998).
These observations have naturally raised questions as to the source and nature of the predominantly CD62L− lymphocytes in circulation following sympathetic activation. The presence of these cells could be due to a preferential release of CD62L− cells into the circulation and/or a loss (shedding) of CD62L from the cell surface. Tedder et al. (1990)demonstrated that approximately 80% of lymphocytes in the spleen and other lymphoid organs do not express CD62L or express it at very low levels. Since the spleen is a major source of circulating lymphocytes following sympathetic stimulation (Benschop et al., 1996), it is reasonable to assume that subset redistribution is a significant source of the increase of circulating CD62L− cells. Regarding shedding as a possible mechanism for the increase in circulating CD62L− cells, few studies have examined the surface density of CD62L and/or soluble levels of CD62L following sympathetic activation. Such measures would help address this issue. Studies examining soluble levels of other adhesion molecules, such as ICAM-1, support the possibility of such a shedding mechanism following sympathetic activation (Jilma et al., 1997; Rehman et al., 1997).
Another question to be addressed from these observations pertains to the immune status of the circulating CD62L− lymphocytes. Investigators have had a longstanding interest in assessing the immunologic significance of the effects of stress, both acute and chronic, on immunity (Benschop et al., 1996; Dhabhar and McEwen, 1997, for reviews). Since L-selectin is typically shed from T-lymphocytes as the cell transitions from a naı̈ve to a post-antigen presented memory T-cell (Tedder et al., 1990; Bevilacqua, 1993), it has been hypothesized, but not directly examined, that sympathetic activation leads to preferential recruitment of memory rather than naı̈ve T cells.
This study was designed to further examine these issues of CD62L expression and T cell memory/naı̈ve status following sympathetic activation as well as other cell adhesion and cell trafficking issues. In addition to CD62L, we assessed CD54 (ICAM-1) and the β2-integrin CD11a. Following cell activation and CD62L shedding, CD54 and CD11a are crucial in the molecular cascade of leukocyte adhesion (Springer, 1990; Bevilacqua, 1993). We wanted to assess possible concurrent effects of sympathetic activation on these additional adhesion molecules. One of the common observations between the prior leukocyte trafficking literature (Van Tits et al., 1990; Murray et al., 1992; Mills et al., 1995; Schedlowski et al., 1996; Benschop et al., 1997) and the current leukocyte trafficking and cell adhesion literature (Carlson et al., 1996; Benschop et al., 1997; Rehman et al., 1997; Mills et al., 1999), is the role of the β2-adrenergic receptor as a mediator of this phenomenon. We therefore utilized an infusion of the non-specific β-adrenergic agonist isoproterenol as a sympathetic stimulus. In order for our data to be more readily utilized in the context of the existing leukocyte trafficking literature, we used a similar panel of leukocyte subsets, namely one including mixed lymphocytes, CD4+ and CD8+ T cells, natural killer (NK) cells and monocytes and granulocytes.
Section snippets
Methods
Twenty-three men and women volunteers (mean age of 37 years (SD=7), range of 21–49 years of age) participated after obtaining written informed consent. All subjects were identified as healthy following a history and physical by a physician and all passed an ECG prior to participation. Volunteers were recruited from the local University community and compensated financially for their participation. The protocol was approved by the University of California, San Diego, Institutional Review Board.
Results
The lymphocyte, monocyte and granulocyte data for the placebo and propranolol studies are presented in Table 1 (with the exception of the sL-selectin findings, data in the table and figures are expressed as cells/μl of whole blood). As expected, under the placebo condition, isoproterenol led to a significant increase in the levels of circulating mixed lymphocytes (F2,40=8.9, P≤0.001), CD8+ T cells (F2,40=8.7, P=0.001) and CD3−CD16+56+ NK cells (F2,40=58, P<0.001) and a decrease in CD4+ T cells (
Discussion
This study examined the effects of the non-specific β agonist isoproterenol on peripheral white cell adhesion molecule expression. Our findings replicate the general literature demonstrating a β-adrenergically mediated effect on lymphocyte subset redistribution (Benschop et al., 1996) and, in addition, replicate and extend more recent studies (Kurokawa et al., 1995; Jordon et al., 1997; Miles et al., 1998; Malm et al., 1999) demonstrating that adhesion molecules differentially affect the
Acknowledgements
The authors are grateful to the support of the Immunogenetics Laboratory at the San Diego Veterans Affairs Medical Center, La Jolla, CA. This work was supported by grants MO1-RR00827, HL-57265 and AG-13332 from the National Institutes of Health.
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