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Clin Exp Immunol 1997; 110:500–508
Circadian rhythm of leucocytes and lymphocyte subsets and its possible correlation
with the function of the autonomic nervous system
S. SUZUKI*†, S. TOYABE*, T. MORODA†, T. TADA†, A. TSUKAHARA†, T. IIAI†, M. MINAGAWA†, S. MARUYAMA†, K. HATAKEYAMA†, K. ENDOH‡ & T. ABO* *Department of Immunology, †First Department of Surgery, and ‡Department of Hygienics, Niigata University School of Medicine, Niigta, Japan (Accepted for publication 28 August 1997) There are physiological variations in the levels of leucocytes. Among these, the circadian rhythm is veryimportant in terms of the magnitude. Since newly identified lymphocyte subsets (i.e. extrathymic Tcells) have recently been detected, a comprehensive study of the circadian rhythm was conducted. Allleucocytes were found to vary in number or proportion with a circadian rhythm and were classified intotwo groups. One group—granulocytes, macrophages, natural killer (NK) cells, extrathymic T cells, gdT cells, and CD8þ subset—showed an increase in the daytime (i.e. daytime rhythm). The other group—T cells, B cells, ab T cells, and CD4þ subset—showed an increase at night. Humans are active and showsympathetic nerve dominance in the daytime. Interestingly, granulocytes and lymphocyte subsets withthe daytime rhythm were found to carry a high density of adrenergic receptors. On the other hand,lymphocyte subsets with the night rhythm carried a high proportion of cholinergic receptors. Reflectingthis situation, exercise prominently increased the number of cells with the daytime rhythm. Theseresults suggest that the levels of leucocytes may be under the regulation of the autonomic nervoussystem.
Keywords
INTRODUCTION
that there are two groups of leucocytes with different peak times ofthe circadian rhythm. One group consists of cells with a daytime It is well known that various immunoparameters vary in number rhythm, namely, cells which increase in number or proportion in and function, depending on physical conditions in the host [1,2].
the daytime. This group includes monocytes, granulocytes, natural One such phenomenon is circadian variation in the number of killer (NK) cells, extrathymic T cells, CD8þ cells, and gd T cells.
leucocytes and lymphocyte subsets in humans and animals [3–5].
The other group comprises cells with a night rhythm, namely, cells In earlier studies, such rhythms of lymphocytes were estimated by which increase in number or proportion at night. This group morphological and other criteria. In a subsequent study, lympho- includes T cells (including ab T cells), B cells, and CD4þ cells.
cyte subsets were estimated by MoAbs, and a unique pattern of the Many, if not all, of the cells with the daytime rhythm tend to circadian rhythm was reported [6–8]. In this study, experiments express a higher level of adrenergic receptors on the surface. In were further conducted for the following purposes: (i) since recent contrast, cells with the night rhythm were found to carry a large studies have revealed the existence of new lymphocyte subsets in proportion of cholinergic receptors on the surface. This raises the humans, i.e. CD56þ T cells and CD57þ T cells of extrathymic possibility that physical activity, which accompanies the high origin [9,10], it is desirable that an overall picture of circadian production of catecholamines or inversely the high production of variation of leucocytes and lymphocyte subsets should be acetylcholine (ACh), determines the rhythm of leucocytes. Sup- obtained; (ii) it should also be elucidated what is the major porting this speculation, it was found that all cells with the daytime factor causing the circadian rhythm of leucocytes and lymphocyte rhythm increased in number after exercise. In conjunction with accumulating evidence for adrenergic and cholinergic receptors on The results obtained in the present study in humans demonstrate leucocytes [11,12], it is concluded that physical activity, a function Correspondence: Toru Abo, Department of Immunology, Niigata Uni- of the autonomic nervous system, causes the circadian rhythm of versity School of Medicine, Asahimachi 1, Niigata 951, Japan.
SUBJECTS AND METHODS
HEPES (Nissui Pharmaceutical Co., Tokyo, Japan) and 2% heat-inactivated newborn calf serum for 90 min at 30ЊC. Cells were then incubated with different concentrations (10–200 pM) of 125I-cya- The subjects in this study were 10 healthy men, their ages ranging nopindolol (125I-CYP; Amersham Corp., Arlington Heights, IL) in from 26 to 48 years. Two of them, subject 1 being 48 years old and a total volume of 600 ml medium [11,12]. After being washed three subject 2 being 28 years old, were also tested after exercise. The times with medium, cell pellets were obtained to measure isotope- samples for a circadian rhythm were taken every 4 h from the binding levels in a gamma counter. Specific 125I-CYP binding was beginning at 8.00 am. All donors worked and slept in bed, in a determined by subtracting the value in the presence of 1 mM propranolol from the total counts in its absence.
Immunoparameters examinedPeripheral blood (5 ml) was aspirated into a heparinized syringe.
Identification of cholinergic receptors on the cell surface Two millilitres of the blood were sent to the Central Laboratory Purified cell fractions (2 × 105 cells) were first incubated with a Unit of Niigata University to examine the numbers and proportions medium containing ACh esterase (AChE) (1·0 U/ml). This incuba- of leucocytes, including granulocytes and lymphocytes, and to tion at 37ЊC for 5 h is critical to eliminate saturated ACh on the cell measure the serum levels of adrenaline and noradrenaline. The surface of leucocytes [15]. Cells were harvested and washed twice enumeration of leucocyte count was usually done within several with medium. FITC-conjugated a-bungarotoxin (a-BT; Sigma hours after sampling. During this time, we confirmed that the result Chemical Co., St Louis, MO) was then added at various concen- trations to the cell pellet for 30 min at 4ЊC. After washing, The remaining 3 ml of the blood was used to determine fluorescence-positive cells were analysed by FACScan. This the levels of various lymphocyte subsets. Mononuclear cells method identified the proportion of cells carrying cholinergic (MNC) were isolated by Ficoll–Isopaque gradient (1·077 g/ml) receptors (i.e. nicotinic acetylcholine receptors; nAChR).
Two-colour immunofluorescence tests were applied to identify lymphocytes subsets, NK cells, extrathymic T cells, and conven- Subjects 1 and 2 ran for 1 h, starting at 2.00 pm. Immunopara- tional T and B cells [10]. Two-colour staining for CD3 and CD16 meters were examined at three points of time, i.e. before, just after, (or CD56 or CD57) identified CD3¹CD16þ NK cells (or CD3¹CD56þ or CD3¹CD57þ NK cells), CD3þCD16þ extrathy-mic T cells (or CD3þCD56þ or CD3þCD57þ extrathymic T cells), and CD3þCD16¹ conventional T cells (or CD3þCD56¹ or Rogers’ method was applied to estimate the rhythmicity [16].
CD3þCD57¹ conventional T cells). Two-colour staining for Student’s t-test was also used to estimate the difference of some CD3 and T cell receptor (TCR) ab (or TCR gd) or for CD3 and CD4 (or CD8) was also performed to identify ab T cells (or gd Tcells) and CD4þ T cells (or CD8þ T cells). CD20þCD5¹ B cellswere identified by two-colour staining for CD20 and CD5. All MoAbs used were obtained from Becton Dickinson (Mountain Circadian rhythm of granulocytes, lymphocytes and monocytes View, CA). The fluorescence-positive cells were analysed by In this study, we first confirmed the pattern of variation in thenumber of leucocytes in the peripheral blood over the 24-h period of a day. Data from five healthy donors are represented (Fig. 1).
To determine the presence of adrenergic or cholinergic receptors Although the number of total leucocytes was seen to be relatively on various cell fractions, cell purification was performed. Mono- constant, the number (as well as the proportion) of granulocytes, cytes were purified from whole MNC by adherence to a plastic lymphocytes and monocytes varied, showing a circadian rhythm.
surface [13]. Granulocytes were isolated from the buffy coat of the The number and proportion of granulocytes and monocytes blood (sedimented by 6% dextran sulphate) by Ficoll–Isopaque increased in the daytime, whereas the number and proportion of gradient centrifugation. All lymphocyte subsets were isolated by lymphocytes increased at night (statistical analysis of these para- the cell sorter after two-colour staining in various combinations of meters is included at the top of Table 2). Since granulocytes and 60% of the total leucocytes, the variation in the number of total leucocytes slightly resembled this variation.
This tendency was previously reported by us as well as by other Plasma at the indicated time was used to measure the concentration investigators [3–8]. Since we have already reported the day-to-day of adrenaline and noradrenaline. Its concentrations were analysed variation and annual variation in some of these factors [16], we did by the high performance liquid chromatography (HPLC) system, as described elsewhere [14]. Preliminary experiments of separatedaliquots in one sample showed us that experiment-to-experiment Stability of the value in experiments In the present study, we enumerated many immunoparameters, namely the proportion of various lymphocyte subsets. To deter-mine the variation of such values between experiments, one sample Measurement of b-adrenergic receptors was separated into three aliquots and the values were enumerated Pre-incubation of 2 × 105 cells with 1 mM propranolol was first independently (Table 1). It was confirmed that the variaton was performed in Eagle’s MEM medium supplemented with 6 mM ᭧ 1997 Blackwell Science Ltd, Clinical and Experimental Immunology, 110:500–508
Table 1. Stability of the value in experiments
Mean and s.d. were obtained from three independent experiments.
staining for CD20 and CD5. Both CD20þCD5¹ B cells and CD20¹CD5þ T cells were evaluated to vary with a circadianrhythm, showing an increase in proportion at night.
Circadian rhythm in the serum level of catecholamines One of the greatest circadian variables is physical activity. It may influence the production level of catecholamines. In these experi- ments, the variation in serum level of catecholamines was first confirmed in five healthy donors (Fig. 3). Sera were obtained at the same times as their circadian rhythms had been examined pre- viously. The levels of both adrenaline and noradrenaline varied with a circadian rhythm, showing an increase in the daytime(P 0·001 in Roger’s method).
Fig. 1. Circadian rhythm in the number and proportion of total leucocytes,
granulocytes, lymphocytes, and monocytes. Five healthy donors were
Cells with daytime rhythm expressed a higher level of adrenergic examined on various immunoparameters every 4 h from the beginning at 8.00 am during the 24-h period of a day. It was confirmed that the numberand proportion of granulocytes and monocytes had daytime rhythm, while Leucocytes are known to express adrenergic receptors on their those of lymphocytes had night rhythm. The same symbols in Figs 1–3 surface. In this regard, it was examined whether the expression indicate data from the same individual.
level of adrenergic receptors on various types of leucocytes wasrelated to the pattern of their circadian variation (Fig. 4a). 125I-CYP(b-adrenergic agonist) was used to identify the specific binding forb-adrenergic receptors with or without pretreatment with propra- Circadian rhythm of lymphocyte subsets was classified into two nolol (1 mM). It was found to be greater on granulocytes than on Two-colour staining in various combinations was conducted to Similarly, specific binding for adrenergic receptors was com- identify lymphocyte subsets in the peripheral blood, e.g. NK cells, pared among various cell fractions purified by the cell sorter (Fig.
extrathymic T cells, and conventional T and B cells. Data from five 4b). Monocytes, granulocytes, NK cells and CD56þ T cells (of healthy subjects are represented (Fig. 2). The significance of the extrathymic origin) showed a greater density of adrenergic recep- rhythms is statistically analysed in Table 2. By two-colour staining tors, whereas lymphocyte subsets, i.e. CD4þ, CD8þ and B cells, for CD3 and CD16 (or CD56 or CD57), CD3¹CD16þ (or CD56þ showed a lower density. Cells which had a clear daytime rhythm or CD57þ) NK cells, CD3þCD16þ (or CD56þ or CD57þ) extra- (i.e. phagocytic cells and NK cells) tended to express a higher level thymic T cells, and CD3þCD16¹ (or CD56¹ or CD57¹) conven- tional T cells were determined. NK cells and extrathymic T cells(except CD3þCD16þ cells) were estimated to vary with a circadianrhythm, showing an increase in the proportion in the daytime. In Cells with night rhythm expressed a higher level of cholinergic contrast, conventional T cells varied with a circadian rhythm, showing an increase in the proportion at night. gd T cells increased We recently established a method of directly identifying nAChR in the daytime, whereas ab T cells increased at night. CD4þ T cells on lymphocytes [15]. Since nAChR on lymphocytes is usually increased at night, whereas CD8þ T cells increased in the daytime.
saturated by ACh itself, pretreatment of lymphocytes with AChE B cells as well as T cells were also identified by two-colour for 5 h is required to induce the specific binding of FITC–a-BT.
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Fig. 2. Circadian rhythm of lymphocyte subsets. Five healthy donors were examined. Natural killer (NK) cells, extrathymic T cells, and
conventional T cells, as well as other lymphocyte subsets, were identified by two-colour staining in various combinations of MoAbs.
Lymphocyte subsets were classified into two groups, namely, a daytime rhythm group (e.g. NK cells and extrathymic T cells) and a night
rhythm group (e.g. conventional T and B cells).
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Table 2. Statistical analysis of immunoparameters
Data are results from 10 donors, including five donors indicated in Figs 1–3 and an additional five donors.
Using this method, the level of cholinergic receptors on purified fractions of lymphocytes was examined (Fig. 5). CD3þ T cells, CD20þ B cells and CD56þ NK cells were found to contain a greater proportion of nAChRþ cells than the proportioncontained by granulocytes. In this study, we showed only a relative Fig. 4. Expression of adrenerigc receptors on leucocytes. (a) Specific
difference in the expression of cholinergic receptors among binding of 125I-cyanopindolol (125I-CYP) on granulocytes (X) and lym- phocytes (W). (b) A comparison of the expression of adrenergic receptorsamong leucocytes and various lymphocyte subsets. The sampling time was10.00 am for the experiments of Figs 4 and 5. Monocytes, granulocytes, NK Exercise induced an increase in the number and proportion of cells, and CD56þ T cells (of extrathymic origin) with the daytime rhythmexpressed a higher level of adrenergic receptors on the surface. The mean and 1 s.d. of the data from three donors are represented.
There was a tendency for the group of cells with the daytimerhythm to have a higher level of adrenergic receptors. If thisfinding is valid, exercise (i.e. high physical activity accompanied before and after exercise (Fig. 6). In both subjects, the number of by a high production of catecholamines) may induce some specific total leucocytes and granulocytes increased substantially at the variation patterns. This possibility was examined in two healthy post-exercise time (i.e. just and 4 h after exercise). Although the subjects who ran for 1 h. The number and proportion of leucocytes proportion of granulocytes decreased just after exercise, their and lymphocyte subsets were enumerated at three points of time absolute number increased slightly. In the case of lymphocytes,the absolute number and proportion transiently increased (just afterexercise), but these retured to normal or even lower levels 4 h after exercise. As shown later, this increase in the number and propor- tion of lymphocytes was due to the increase in the number and proportion of NK cells and extrathymic T cells.
All proportional increases of lymphocyte subsets seen after exercise were for cells with daytime rhythm The variation in the proportion of lymphocyte subsets was then examined after exercise (Fig. 7). The proportion of NKcells and extrathymic T cells increased just after exercise, without exception, in both subjects. In sharp contrast, the proportion ofconventional T cells decreased prominently. Similarly with regard Fig. 3. Circadian variation in the serum levels of adrenaline (a) and
to the circadian rhythm, the proportion of gd T cells increased, noradrenaline (b). To confirm whether physical activity changes the function of the sympathetic nervous system, catecholamine levels in the blood were examined in five healthy donors.
exercise induced an increase in the proportion of the subsets ᭧ 1997 Blackwell Science Ltd, Clinical and Experimental Immunology, 110:500–508
Fig. 6. Variation in the number or proportion of granulocytes and lympho-
Fig. 5. A comparison of the expression of cholinergic receptors among
cytes after exercise. Two healthy subjects ran for 1 h and various immu- leucocytes and lymphocyte subsets. All cells were pre-incubated with noparameters in the peripheral blood were examined at the indicated points 1·0 U/ml acetylcholine esterase (AChE) for 5 h and then stained with of time. Just after exercise, the number of lymphocytes increased and that of FITC-conjugated a-bungarotoxin (a-BT). There was an order in the granulocytes gradually increased thereafter. Subsequent experiments (see expression level of nicotinic acetylcholine receptor (nAChR), i.e. CD20þ Fig. 7) revealed that the increase of lymphocytes was due to that of NK B cells CD3þ T cells CD56þ NK cells granulocytes. Representative cells. The sampling for the experiments of Fig. 6 was started at 2.00 pm.
results from three experiments are depicted.
with the daytime rhythm. The levels of T cells estimated by this situation, total CD8þ cells may behave as the cells with CD8 and CD20þCD5¹ B cells were relatively stationary after The next objective of this study was to determine what causes the circadian rhythm of leucocytes in the body. Previously, wefound that mice (which are nocturnal) have a circadian rhythm of DISCUSSION
lymphocytes in all tested organs, which is opposite to that of In this study, we first confirmed that granulocytes and monocytes humans [17]. A secretion burst of glucocorticoids is seen in both varied in number and proportion, showing a circadian rhythm with humans and mice just before the start of physical activity (e.g. an a peak in the daytime (i.e. daytime rhythm), whereas total lym- early morning secretion of glucocorticoids in humans) [5]. In other phocytes showed a peak at night (i.e. night rhythm). Based on this words, the early morning secretion of glucocorticoids stimulates earlier evidence [3–8], experiments were then conducted to and awakes us, and results in the subsequent daily rhythm of our characterize the rhythm of various lymphocyte subsets, including activity, accompanying the serum elevation of catecholamines.
possible extrathymic T cells (i.e. CD56þ T cells and CD57þ T Therefore, we used adrenalectomized mice in an attempt to cells) [9,10]. It was found that cell populations could be classified identify possible influences on the circadian rhythm [17]. These into two groups: one group with daytime rhythm includes granu- mice lost such circadian rhythms, implying some hormonal reg- locytes, monocytes, NK cells, extrathymic T cells, gd T cells, and ulation. However, because of impaired mobility, they also lost the CD8þ cells. The other, with night rhythm, includes conventional T variation of their physical activity round the clock. Changes in the and B cells, ab T cells, and CD4þ cells. It is well known that NK activity of the autonomic nervous system might affect leucocyte cells, extrathymic T cells and gd T cells are involved in natural subsets, some of them carrying adrenergic or cholinergic receptors immunity and are more primitive than conventional T (and ab T) [11,12]. There are many reports on changes in blood leucocytes and B cells in phylogenetic development. Therefore, cell popula- tions with daytime rhythm might belong to a primitive lineage of receptors among leucocytes and various lymphocyte subsets in CD8þ cells consist of both conventional T cells and extra- this study. There was a tendency for cells with daytime rhythm thymic T cells. In usually healthy pearsons, CD8þ extrathymic T to express a higher density of adrenergic receptors on the cells are much more dominant than CD8þ conventional T cells. In surface, while cells with night rhythm were found to express a ᭧ 1997 Blackwell Science Ltd, Clinical and Experimental Immunology, 110:500–508
Fig. 7. Variation in the proportion of lymphocyte subsets after exercise. Two healthy subjects ran for 1 h and various immunoparameters in the
peripheral blood were exmained at the indicated points of time. Exercies induced an increase in the proportion of cells with the daytim rhythm
(i.e. cells carrying a higher level of adrenergic receptors), although there was a time lag (e.g. granulocytes).
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