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Research Highlights

Issa, Fadi, MRCS, DPhil

doi: 10.1097/TP.0000000000002628
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Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

Received 14 January 2019.

The author declares no funding or conflicts of interest.

Admin Staff is never an author of any feature.

Correspondence: Fadi Issa, MRCS, DPhil, Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom. (fadi.issa@nds.ox.ac.uk).

He W, Holtkamp S, Hergenhan SM, et al. Circadian Expression of Migratory Factors Establishes Lineage-Specific Signatures That Guide the Homing of Leukocyte Subsets to Tissues. Immunity. 2018;49:1175-1190.e7.

Circadian rhythms are controlled by the suprachiasmatic nucleus and have an impact on a number of physiological processes including the sleep/wake cycle, locomotor function, metabolism, and circulatory function.1 There are very important implications for transplantation, where aberrations in the central clock have detrimental effects on glucose and lipid metabolism as well as blood pressure regulation. Remarkably, dysfunction of the circadian clock within transplanted tissue has been found to contribute to the development of transplant arteriosclerosis—irrespective of the function of the host clock.2 Those aspects highlight potentially important effects of the central clock on immune function, with data indicating a clear variation of leukocyte numbers in the circulation depending on the time of day.3 In their recent publication in Immunity, He et al4 explore this variation further using an organism-wide screening approach. Leukocyte emigration was found to oscillate over a 24-hour period, with cells peaking in the morning and a trough in the evening. Fascinatingly, this circadian effect was accompanied by changes in the expression of leukocyte adhesion molecules on tissue endothelium, therefore directing immune cell populations toward certain organs at specific times. When clock function was ablated through deletion of the critical circadian transcription factor BMAL-1 in either tissues or leukocytes, this resulted in a loss of oscillatory migratory function. In a model of inflammation, blockade of rhythmic leukocyte trafficking resulted in change of the immune response. The authors found similar oscillations of leukocytes in humans, although the pattern was inverted, with higher numbers in the blood in the evening. While the implications for transplantation require further investigation, there are clearly areas of interest related to timing of surgery and when to aim for peaks and troughs of immunosuppression.

1.Ralph MR, Foster RG, Davis FC, et al. Transplanted suprachiasmatic nucleus determines circadian period. Science. 1990;247(4945):975-978.

2.Cheng B, Anea CB, Yao L, et al. Tissue-intrinsic dysfunction of circadian clock confers transplant arteriosclerosis. Proc Natl Acad Sci U S A. 2011;108(41):17147-17152. doi: 10.1073/pnas.1112998108.

3.Scheiermann C, Kunisaki Y, Frenette PS. Circadian control of the immune system. Nat Rev Immunol. 2013;13(3):190-198. doi: 10.1038/nri3386.

4.He W, Holtkamp S, Hergenhan SM, et al. Circadian expression of migratory factors establishes lineage-specific signatures that guide the homing of leukocyte subsets to tissues. Immunity. 2018;49(6):1175-1190.e7. doi: 10.1016/j.immuni.2018.10.007.

Peterson LB, Bell CJM, Howlett SK, et al. A Long-Lived IL-2 Mutein That Selectively Activates and Expands Regulatory T Cells as a Therapy for Autoimmune Disease. J Autoimmun. 2018;95:1-14.

Interleukin (IL)-2 is a pleiotropic cytokine with key activity in the differentiation and function of both effector and regulatory T cells (Tregs) through the control of transcriptional and metabolic programs.1 IL-2 is necessary for Treg function and proliferation, acting through the high-affinity IL-2 receptor (IL-2R, CD25). The IL-2 receptor is a heterotrimeric receptor consisting of α-, β-, and γ-chains. Several studies have examined therapeutic IL-2 administration at doses thought to preferentially act on Tregs. IL-2 has also been shown to reverse the detrimental effects of calcineurin inhibitors on Tregs, by enhancing the expression of antiapoptotic molecules.2

Recombinant human IL-2 (aldesleukin) has been trialled in a number of conditions, including SLE3 and diabetes.4 This approach represents an attractive therapeutic prospect as it bypasses the requirement for adoptive cellular therapy by directly expanding Tregs in vivo. However, a challenge remains in the identification of an appropriate dose that acts more specifically on Tregs rather than effector T cells. Peterson et al5 present data on an IL-2 variant with higher specificity for Tregs, by decreasing its affinity for the IL-2Rβ-chain which effector T cells preferentially signal through. This IL-2 mutein was shown to be highly selective for human Tregs in vitro and in vivo in cynomolgus monkeys and humanized mice. This approach is of significant interest, particularly given the genuine risk of expanding nonregulatory cell populations with recombinant IL-2 treatment. Other IL-2 muteins are currently under investigation, including Celgene’s DEL106 which was developed by Delinia. Clinical trials of recombinant IL-2 therapy in transplantation are currently ongoing and results from these are anticipated. Future trials may also consider the use of these more selective IL-2 muteins.

1.Ross SH, Cantrell DA. Signaling and function of interleukin-2 in t lymphocytes. Annu Rev Immunol. 2018;36:411-433. doi: 10.1146/annurev-immunol-042617-053352.

2.Whitehouse G, Gray E, Mastoridis S, et al. il-2 therapy restores regulatory t-cell dysfunction induced by calcineurin inhibitors. Proc Natl Acad Sci U S A. 2017;114(27):7083-7088. doi: 10.1073/pnas.1620835114.

3.He J, Zhang X, Wei Y, et al. Low-dose interleukin-2 treatment selectively modulates CD4(+) t cell subsets in patients with systemic lupus erythematosus. Nat Med. 2016;22(9):991-993. doi: 10.1038/nm.4148.

4.Todd JA, Evangelou M, Cutler AJ, et al. Regulatory t cell responses in participants with type 1 diabetes after a single dose of interleukin-2: a non-randomised, open label, adaptive dose-finding trial. Plos Med. 2016;13(10):e1002139. doi: 10.1371/journal.pmed.1002139.

5.Peterson LB, Bell CJM, Howlett SK, et al. a long-lived il-2 mutein that selectively activates and expands regulatory t cells as a therapy for autoimmune disease. J Autoimmun. 2018;95:1-14. doi: 10.1016/j.jaut.2018.10.017.

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