Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2017

Open Access 01-12-2017 | Research

γδT cells but not αβT cells contribute to sepsis-induced white matter injury and motor abnormalities in mice

Authors: Xiaoli Zhang, Eridan Rocha-Ferreira, Tao Li, Regina Vontell, Darakhshan Jabin, Sha Hua, Kai Zhou, Arshed Nazmi, Anna-Maj Albertsson, Kristina Sobotka, Joakim Ek, Claire Thornton, Henrik Hagberg, Carina Mallard, Jianmei W. Leavenworth, Changlian Zhu, Xiaoyang Wang

Published in: Journal of Neuroinflammation | Issue 1/2017

Login to get access

Abstract

Background

Infection and sepsis are associated with brain white matter injury in preterm infants and the subsequent development of cerebral palsy.

Methods

In the present study, we used a neonatal mouse sepsis-induced white matter injury model to determine the contribution of different T cell subsets (αβT cells and γδT cells) to white matter injury and consequent behavioral changes. C57BL/6J wild-type (WT), T cell receptor (TCR) δ-deficient (Tcrd −/−, lacking γδT cells), and TCRα-deficient (Tcra −/−, lacking αβT cells) mice were administered with lipopolysaccharide (LPS) at postnatal day (PND) 2. Brain myelination was examined at PNDs 12, 26, and 60. Motor function and anxiety-like behavior were evaluated at PND 26 or 30 using DigiGait analysis and an elevated plus maze.

Results

White matter development was normal in Tcrd −/− and Tcrα −/− compared to WT mice. LPS exposure induced reductions in white matter tissue volume in WT and Tcrα −/− mice, but not in the Tcrd −/− mice, compared with the saline-treated groups. Neither LPS administration nor the T cell deficiency affected anxiety behavior in these mice as determined with the elevated plus maze. DigiGait analysis revealed motor function deficiency after LPS-induced sepsis in both WT and Tcrα −/− mice, but no such effect was observed in Tcrd −/− mice.

Conclusions

Our results suggest that γδT cells but not αβT cells contribute to sepsis-induced white matter injury and subsequent motor function abnormalities in early life. Modulating the activity of γδT cells in the early stages of preterm white matter injury might represent a novel therapeutic strategy for the treatment of perinatal brain injury.
Appendix
Available only for authorised users
Literature
1.
Wu YW, Colford JM Jr. Chorioamnionitis as a risk factor for cerebral palsy: a meta-analysis. JAMA. 2000;284:1417–24.CrossRefPubMed
2.
Dammann O, Leviton A. Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn. Pediatr Res. 1997;42:1–8.CrossRefPubMed
3.
Hagberg H, Gressens P, Mallard C. Inflammation during fetal and neonatal life: implications for neurologic and neuropsychiatric disease in children and adults. Ann Neurol. 2012;71:444–57.CrossRefPubMed
4.
Hagberg H, Mallard C, Ferriero DM, Vannucci SJ, Levison SW, Vexler ZS, Gressens P. The role of inflammation in perinatal brain injury. Nat Rev Neurol. 2015;11:192–208.CrossRefPubMedPubMedCentral
5.
Strunk T, Inder T, Wang X, Burgner D, Mallard C, Levy O. Infection-induced inflammation and cerebral injury in preterm infants. Lancet Infect Dis. 2014;14:751–62.CrossRefPubMedPubMedCentral
6.
7.
8.
Craig A, Ling Luo N, Beardsley DJ, Wingate-Pearse N, Walker DW, Hohimer AR, Back SA. Quantitative analysis of perinatal rodent oligodendrocyte lineage progression and its correlation with human. Exp Neurol. 2003;181:231–40.CrossRefPubMed
9.
Nobuta H, Ghiani CA, Paez PM, Spreuer V, Dong H, Korsak RA, Manukyan A, Li J, Vinters HV, Huang EJ, et al. STAT3-mediated astrogliosis protects myelin development in neonatal brain injury. Ann Neurol. 2012;72:750–65.CrossRefPubMedPubMedCentral
10.
Wang X, Rousset CI, Hagberg H, Mallard C. Lipopolysaccharide-induced inflammation and perinatal brain injury. Semin Fetal Neonatal Med. 2006;11:343–53.CrossRefPubMed
11.
Cardoso FL, Herz J, Fernandes A, Rocha J, Sepodes B, Brito MA, McGavern DB, Brites D. Systemic inflammation in early neonatal mice induces transient and lasting neurodegenerative effects. J Neuroinflammation. 2015;12:82.CrossRefPubMedPubMedCentral
12.
Wang X, Hellgren G, Lofqvist C, Li W, Hellstrom A, Hagberg H, Mallard C. White matter damage after chronic subclinical inflammation in newborn mice. J Child Neurol. 2009;24:1171–8.CrossRefPubMedPubMedCentral
13.
Zanin-Zhorov A, Tal-Lapidot G, Cahalon L, Cohen-Sfady M, Pevsner-Fischer M, Lider O, Cohen IR. Cutting edge: T cells respond to lipopolysaccharide innately via TLR4 signaling. J Immunol. 2007;179:41–4.CrossRefPubMed
14.
Molteni M, Gemma S, Rossetti C. The role of Toll-like receptor 4 in infectious and noninfectious inflammation. Mediat Inflamm. 2016;2016:6978936.CrossRef
15.
Gibbons D, Fleming P, Virasami A, Michel ML, Sebire NJ, Costeloe K, Carr R, Klein N, Hayday A. Interleukin-8 (CXCL8) production is a signatory T cell effector function of human newborn infants. Nat Med. 2014;20:1206–10.CrossRefPubMed
16.
Conti L, Casetti R, Cardone M, Varano B, Martino A, Belardelli F, Poccia F, Gessani S. Reciprocal activating interaction between dendritic cells and pamidronate-stimulated gammadelta T cells: role of CD86 and inflammatory cytokines. J Immunol. 2005;174:252–60.CrossRefPubMed
17.
Devilder MC, Maillet S, Bouyge-Moreau I, Donnadieu E, Bonneville M, Scotet E. Potentiation of antigen-stimulated V gamma 9V delta 2 T cell cytokine production by immature dendritic cells (DC) and reciprocal effect on DC maturation. J Immunol. 2006;176:1386–93.CrossRefPubMed
18.
Devilder MC, Allain S, Dousset C, Bonneville M, Scotet E. Early triggering of exclusive IFN-gamma responses of human Vgamma9Vdelta2 T cells by TLR-activated myeloid and plasmacytoid dendritic cells. J Immunol. 2009;183:3625–33.CrossRefPubMed
19.
Vincze A, Mazlo M, Seress L, Komoly S, Abraham H. A correlative light and electron microscopic study of postnatal myelination in the murine corpus callosum. Int J Dev Neurosci. 2008;26:575–84.CrossRefPubMed
20.
Wang X, Hagberg H, Nie C, Zhu C, Ikeda T, Mallard C. Dual role of intrauterine immune challenge on neonatal and adult brain vulnerability to hypoxia-ischemia. J Neuropathol Exp Neurol. 2007;66:552–61.CrossRefPubMed
21.
Bi D, Qiao L, Bergelson I, Ek CJ, Duan L, Zhang X, Albertsson AM, Pettengill M, Kronforst K, Ninkovic J, et al. Staphylococcus epidermidis bacteremia induces brain injury in neonatal mice via Toll-like receptor 2-dependent and -independent pathways. J Infect Dis. 2015;212(9):1480–1490.
22.
Wang X, Carlsson Y, Basso E, Zhu C, Rousset CI, Rasola A, Johansson BR, Blomgren K, Mallard C, Bernardi P, et al. Developmental shift of cyclophilin D contribution to hypoxic-ischemic brain injury. J Neurosci. 2009;29:2588–96.CrossRefPubMedPubMedCentral
23.
24.
Hansen ST, Pulst SM. Response to ethanol induced ataxia between C57BL/6J and 129X1/SvJ mouse strains using a treadmill based assay. Pharmacol Biochem Behav. 2013;103:582–8.CrossRefPubMed
25.
Franco-Pons N, Torrente M, Colomina MT, Vilella E. Behavioral deficits in the cuprizone-induced murine model of demyelination/remyelination. Toxicol Lett. 2007;169:205–13.CrossRefPubMed
26.
Hermans RH, Hunter DE, McGivern RF, Cain CD, Longo LD. Behavioral sequelae in young rats of acute intermittent antenatal hypoxia. Neurotoxicol Teratol. 1992;14:119–29.CrossRefPubMed
27.
Fernagut PO, Diguet E, Labattu B, Tison F. A simple method to measure stride length as an index of nigrostriatal dysfunction in mice. J Neurosci Methods. 2002;113:123–30.CrossRefPubMed
28.
Wooley CM, Xing S, Burgess RW, Cox GA, Seburn KL. Age, experience and genetic background influence treadmill walking in mice. Physiol Behav. 2009;96:350–61.CrossRefPubMed
29.
Wang X, Han W, Du X, Zhu C, Carlsson Y, Mallard C, Jacotot E, Hagberg H. Neuroprotective effect of Bax-inhibiting peptide on neonatal brain injury. Stroke. 2010;41:2050–5.CrossRefPubMed
30.
Lavelle EC, Murphy C, O’Neill LA, Creagh EM. The role of TLRs, NLRs, and RLRs in mucosal innate immunity and homeostasis. Mucosal Immunol. 2010;3:17–28.CrossRefPubMed
31.
Tsung A, Sahai R, Tanaka H, Nakao A, Fink MP, Lotze MT, Yang H, Li J, Tracey KJ, Geller DA, Billiar TR. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J Exp Med. 2005;201:1135–43.CrossRefPubMedPubMedCentral
32.
Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, Prestwich GD, Mascarenhas MM, Garg HG, Quinn DA, et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med. 2005;11:1173–9.CrossRefPubMed
33.
Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 2006;116:3015–25.CrossRefPubMedPubMedCentral
34.
Dar AA, Patil RS, Chiplunkar SV. Insights into the relationship between Toll like receptors and gamma delta T cell responses. Front Immunol. 2014;5:366.CrossRefPubMedPubMedCentral
35.
Wesch D, Peters C, Oberg HH, Pietschmann K, Kabelitz D. Modulation of gammadelta T cell responses by TLR ligands. Cell Mol Life Sci. 2011;68:2357–70.CrossRefPubMed
36.
Lee HH, Hoeman CM, Hardaway JC, Guloglu FB, Ellis JS, Jain R, Divekar R, Tartar DM, Haymaker CL, Zaghouani H. Delayed maturation of an IL-12-producing dendritic cell subset explains the early Th2 bias in neonatal immunity. J Exp Med. 2008;205:2269–80.CrossRefPubMedPubMedCentral
37.
38.
Mottahedin A, Smith PL, Hagberg H, Ek CJ, Mallard C. TLR2-mediated leukocyte trafficking to the developing brain. J Leukoc Biol. 2017;101:297–305.CrossRefPubMed
39.
40.
41.
Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, Iwaki T, Okada Y, Iida M, Cua DJ, et al. Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nat Med. 2009;15:946–50.CrossRefPubMed
42.
Chien YH, Meyer C, Bonneville M. Gammadelta T cells: first line of defense and beyond. Annu Rev Immunol. 2014;32:121–55.CrossRefPubMed
43.
Carding SR, Kyes S, Jenkinson EJ, Kingston R, Bottomly K, Owen JJ, Hayday AC. Developmentally regulated fetal thymic and extrathymic T-cell receptor gamma delta gene expression. Genes Dev. 1990;4:1304–15.CrossRefPubMed
44.
Pardoll DM, Fowlkes BJ, Bluestone JA, Kruisbeek A, Maloy WL, Coligan JE, Schwartz RH. Differential expression of two distinct T-cell receptors during thymocyte development. Nature. 1987;326:79–81.CrossRefPubMed
45.
McVay LD, Carding SR. Extrathymic origin of human gamma delta T cells during fetal development. J Immunol. 1996;157:2873–82.PubMed
46.
Levy O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev Immunol. 2007;7:379–90.CrossRefPubMed
47.
Kumar SK, Bhat BV. Distinct mechanisms of the newborn innate immunity. Immunol Lett. 2016;173:42–54.CrossRefPubMed
48.
Adkins B, Leclerc C, Marshall-Clarke S. Neonatal adaptive immunity comes of age. Nat Rev Immunol. 2004;4:553–64.CrossRefPubMed
49.
Larsson R, Rocksen D, Lilliehook B, Jonsson A, Bucht A. Dose-dependent activation of lymphocytes in endotoxin-induced airway inflammation. Infect Immun. 2000;68:6962–9.CrossRefPubMedPubMedCentral
50.
Enoh VT, Lin SH, Lin CY, Toliver-Kinsky T, Murphey ED, Varma TK, Sherwood ER. Mice depleted of alphabeta but not gammadelta T cells are resistant to mortality caused by cecal ligation and puncture. Shock. 2007;27:507–19.CrossRefPubMed
51.
Tschop J, Martignoni A, Goetzman HS, Choi LG, Wang Q, Noel JG, Ogle CK, Pritts TA, Johannigman JA, Lentsch AB, Caldwell CC. Gammadelta T cells mitigate the organ injury and mortality of sepsis. J Leukoc Biol. 2008;83:581–8.CrossRefPubMed
52.
Rilett KC, Friedel M, Ellegood J, MacKenzie RN, Lerch JP, Foster JA. Loss of T cells influences sex differences in behavior and brain structure. Brain Behav Immun. 2015;46:249–60.CrossRefPubMed
53.
Drobyshevsky A, Bregman J, Storey P, Meyer J, Prasad PV, Derrick M, MacKendrick W, Tan S. Serial diffusion tensor imaging detects white matter changes that correlate with motor outcome in premature infants. Dev Neurosci. 2007;29:289–301.CrossRefPubMed
54.
Fowler EG, Goldberg EJ. The effect of lower extremity selective voluntary motor control on interjoint coordination during gait in children with spastic diplegic cerebral palsy. Gait Posture. 2009;29:102–7.CrossRefPubMed
55.
Fetters L, Chen YP, Jonsdottir J, Tronick EZ. Kicking coordination captures differences between full-term and premature infants with white matter disorder. Hum Mov Sci. 2004;22:729–48.CrossRefPubMed
56.
Fetters L, Sapir I, Chen YP, Kubo M, Tronick E. Spontaneous kicking in full-term and preterm infants with and without white matter disorder. Dev Psychobiol. 2010;52:524–36.CrossRefPubMed
57.
Baezner H, Blahak C, Poggesi A, Pantoni L, Inzitari D, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Langhorne P, et al. Association of gait and balance disorders with age-related white matter changes: the LADIS study. Neurology. 2008;70:935–42.CrossRefPubMed
58.
Starr JM, Leaper SA, Murray AD, Lemmon HA, Staff RT, Deary IJ, Whalley LJ. Brain white matter lesions detected by magnetic resonance [correction of resosnance] imaging are associated with balance and gait speed. J Neurol Neurosurg Psychiatry. 2003;74:94–8.CrossRefPubMedPubMedCentral
59.
Brod S, Rattazzi L, Piras G, D’Acquisto F. ‘As above, so below’ examining the interplay between emotion and the immune system. Immunology. 2014;143:311–8.CrossRefPubMedPubMedCentral
60.
Kim SJ, Lee H, Lee G, Oh SJ, Shin MK, Shim I, Bae H. CD4+CD25+ regulatory T cell depletion modulates anxiety and depression-like behaviors in mice. PLoS One. 2012;7:e42054.CrossRefPubMedPubMedCentral
Metadata
Title
γδT cells but not αβT cells contribute to sepsis-induced white matter injury and motor abnormalities in mice
Authors
Xiaoli Zhang
Eridan Rocha-Ferreira
Tao Li
Regina Vontell
Darakhshan Jabin
Sha Hua
Kai Zhou
Arshed Nazmi
Anna-Maj Albertsson
Kristina Sobotka
Joakim Ek
Claire Thornton
Henrik Hagberg
Carina Mallard
Jianmei W. Leavenworth
Changlian Zhu
Xiaoyang Wang
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-017-1029-9

Other articles of this Issue 1/2017

Journal of Neuroinflammation 1/2017 Go to the issue

Research

Pharmacologic activation of cholinergic alpha7 nicotinic receptors mitigates depressive-like behavior in a mouse model of chronic stress

Research

Early strong intrathecal inflammation in cerebellar type multiple system atrophy by cerebrospinal fluid cytokine/chemokine profiles: a case control study

Research

MicroRNA expression changes in association with changes in interleukin-1ß/interleukin10 ratios produced by monocytes in autism spectrum disorders: their association with neuropsychiatric symptoms and comorbid conditions (observational study)

Research

MHC class II expression and potential antigen-presenting cells in the retina during experimental autoimmune uveitis

Research

Sex-dependent treatment of chronic EAE with partial MHC class II constructs

Research

Microglial-derived miRNA let-7 and HMGB1 contribute to ethanol-induced neurotoxicity via TLR7