Editors' ChoiceImmunology

Circadian effects on immunization responses

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Sci. Signal.  06 Dec 2016:
Vol. 9, Issue 457, pp. ec285
DOI: 10.1126/scisignal.aal5222

As part of the adaptive immune system, lymphocytes travel through lymph nodes in search of antigens. The cells then pass into the lymph and reenter the blood before recycling back through other lymph nodes or trafficking to tissues to mediate immune responses. Noting that cells of the innate immune system, such as neutrophils and monocytes, exhibit circadian control of their migration from the blood to tissues, Suzuki et al. examined the trafficking of lymphocytes in mice housed in a 12-hour light/12-hour dark cycle. Previous work showed that noradrenaline released from adrenergic nerves in lymphoid tissue stimulates the β2-adrenergic receptor (β2AR) on T cells, which enhances the responsiveness of two chemokine receptors (CCR7 and CXCR4) that promote the retention of T cells in the lymph nodes. The authors found that the numbers of B cells and CD4+ and CD8+ T cells in the blood were maximal in the mice 5 hours into the light period and decreased about 1 hour after the light was switched off. In contrast, the numbers of lymphocytes in peripheral lymph nodes were maximal after 1 to 5 hours of the dark period. The amount of noradrenaline in the lymph nodes was also maximal during the dark period. Mice administered the neurotoxin 6-OHDA, which depletes adrenergic nerves, failed to exhibit increased lymphocyte numbers in lymph nodes during the dark period. Furthermore, β2AR-deficient lymphocytes did not show diurnal regulation of lymph node trafficking when transferred into wild-type mice. Concentrations of antibodies specific for the antigen NP-CGG were greater in mice that were immunized 5 hours into the dark period than in mice that were immunized 5 hours into the light period, suggesting that the increased numbers of lymphocytes in the lymph nodes in the dark enhanced the immune response to the antigen. These differences in antibody production between immunization in the light or dark were lost in 6-OHDA–treated or β2AR-deficient mice. These data suggest that the control of lymphocyte trafficking through lymph nodes by adrenergic nerves determines the strength of antibody-based immune responses, findings that might be of therapeutic benefit in the context of clinical vaccination.

K. Suzuki, Y. Hayano, A. Nakai, F. Furuta, M. Noda, Adrenergic control of the adaptive immune response by diurnal lymphocyte recirculation through lymph nodes. J. Exp. Med. 213, 2567–2574 (2016). [PubMed]