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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2020

01-12-2020 | Nerve Injury | Research

CD4+ T cell expression of the IL-10 receptor is necessary for facial motoneuron survival after axotomy

Authors: Elizabeth M. Runge, Abhirami K. Iyer, Deborah O. Setter, Felicia M. Kennedy, Virginia M. Sanders, Kathryn J. Jones

Published in: Journal of Neuroinflammation | Issue 1/2020

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Abstract

Background

After peripheral nerve transection, facial motoneuron (FMN) survival depends on an intact CD4+ T cell population and a central source of interleukin-10 (IL-10). However, it has not been determined previously whether CD4+ T cells participate in the central neuroprotective IL-10 cascade after facial nerve axotomy (FNA).

Methods

Immunohistochemical labeling of CD4+ T cells, pontine vasculature, and central microglia was used to determine whether CD4+ T cells cross the blood-brain barrier and enter the facial motor nucleus (FMNuc) after FNA. The importance of IL-10 signaling in CD4+ T cells was assessed by performing adoptive transfer of IL-10 receptor beta (IL-10RB)-deficient CD4+ T cells into immunodeficient mice prior to injury. Histology and qPCR were utilized to determine the impact of IL-10RB-deficient T cells on FMN survival and central gene expression after FNA. Flow cytometry was used to determine whether IL-10 signaling in T cells was necessary for their differentiation into neuroprotective subsets.

Results

CD4+ T cells were capable of crossing the blood-brain barrier and associating with reactive microglial nodules in the axotomized FMNuc. Full induction of central IL-10R gene expression after FNA was dependent on CD4+ T cells, regardless of their own IL-10R signaling capability. Surprisingly, CD4+ T cells lacking IL-10RB were incapable of mediating neuroprotection after axotomy and promoted increased central expression of genes associated with microglial activation, antigen presentation, T cell co-stimulation, and complement deposition. There was reduced differentiation of IL-10RB-deficient CD4+ T cells into regulatory CD4+ T cells in vitro.

Conclusions

These findings support the interdependence of IL-10- and CD4+ T cell-mediated mechanisms of neuroprotection after axotomy. CD4+ T cells may potentiate central responsiveness to IL-10, while IL-10 signaling within CD4+ T cells is necessary for their ability to rescue axotomized motoneuron survival. We propose that loss of IL-10 signaling in CD4+ T cells promotes non-neuroprotective autoimmunity after FNA.
Literature
1.
Serpe CJ, Kohm AP, Huppenbauer CB, Sanders VM, Jones KJ. Exacerbation of facial motoneuron loss after facial nerve transection in severe combined immunodeficient (scid) mice. J Neurosci. 1999;19(11):RC7.PubMedPubMedCentralCrossRef
2.
Serpe CJ, Sanders VM, Jones KJ. Kinetics of facial motoneuron loss following facial nerve transection in severe combined immunodeficient mice. J Neurosci Res. 2000;62(2):273–8.PubMedCrossRef
3.
Serpe CJ, Coers S, Sanders VM, Jones KJ. CD4+ T, but not CD8+ or B, lymphocytes mediate facial motoneuron survival after facial nerve transection. Brain Behav Immun. 2003;17(5):393–402.PubMedCrossRef
4.
Deboy CA, Xin J, Byram SC, Serpe CJ, Sanders VM, Jones KJ. Immune-mediated neuroprotection of axotomized mouse facial motoneurons is dependent on the IL-4/STAT6 signaling pathway in CD4(+) T cells. Exp Neurol. 2006;201(1):212–24.PubMedCrossRef
5.
Setter DO, Runge EM, Schartz ND, Kennedy FM, Brown BL, McMillan KP, et al. Impact of peripheral immune status on central molecular responses to facial nerve axotomy. Brain Behav Immun. 2018;68:98–110.PubMedCrossRef
6.
Byram SC, Carson MJ, DeBoy CA, Serpe CJ, Sanders VM, Jones KJ. CD4-positive T cell-mediated neuroprotection requires dual compartment antigen presentation. J Neurosci. 2004;24(18):4333–9.PubMedPubMedCentralCrossRef
7.
Wainwright DA, Xin J, Mesnard NA, Beahrs TR, Politis CM, Sanders VM, et al. Exacerbation of facial motoneuron loss after facial nerve axotomy in CCR3-deficient mice. ASN Neuro. 2009;1(5):e00024.PubMedPubMedCentralCrossRef
8.
Wainwright DA, Mesnard NA, Xin J, Sanders VM, Jones KJ. Effects of facial nerve axotomy on Th2-associated and Th1-associated chemokine mRNA expression in the facial motor nucleus of wild-type and presymptomatic SOD1 mice. J Neurodegener Regen. 2009;2(1):39–44.PubMedPubMedCentral
9.
Wainwright DA, Xin J, Mesnard NA, Politis CM, Sanders VM, Jones KJ. Effects of facial nerve axotomy on Th2- and Th1-associated chemokine expression in the facial motor nucleus of wild-type and presymptomatic mSOD1 mice. J Neuroimmunol. 2009;216(1-2):66–75.PubMedPubMedCentralCrossRef
10.
Petitto JM, Huang Z, Lo J, Streit WJ. IL-2 gene knockout affects T lymphocyte trafficking and the microglial response to regenerating facial motor neurons. J Neuroimmunol. 2003;134(1-2):95–103.PubMedCrossRef
11.
Raivich G, Jones LL, Kloss CU, Werner A, Neumann H, Kreutzberg GW. Immune surveillance in the injured nervous system: T-lymphocytes invade the axotomized mouse facial motor nucleus and aggregate around sites of neuronal degeneration. J Neurosci. 1998;18(15):5804–16.PubMedPubMedCentralCrossRef
12.
Dauer DJ, Huang Z, Ha GK, Kim J, Khosrowzadeh D, Petitto JM. Age and facial nerve axotomy-induced T cell trafficking: relation to microglial and motor neuron status. Brain Behav Immun. 2011;25(1):77–82.PubMedCrossRef
13.
Graeber MB, Tetzlaff W, Streit WJ, Kreutzberg GW. Microglial cells but not astrocytes undergo mitosis following rat facial nerve axotomy. Neurosci Lett. 1988;85(3):317–21.PubMedCrossRef
14.
Torvik A, Skjorten F. Electron microscopic observations on nerve cell regeneration and degeneration after axon lesions. II. Changes in the glial cells. Acta Neuropathol. 1971;17(3):265–82.PubMedCrossRef
15.
Streit WJ, Graeber MB, Kreutzberg GW. Peripheral nerve lesion produces increased levels of major histocompatibility complex antigens in the central nervous system. J Neuroimmunol. 1989;21(2-3):117–23.PubMedPubMedCentralCrossRef
16.
Bohatschek M, Kloss CU, Hristova M, Pfeffer K, Raivich G. Microglial major histocompatibility complex glycoprotein-1 in the axotomized facial motor nucleus: regulation and role of tumor necrosis factor receptors 1 and 2. J Comp Neurol. 2004;470(4):382–99.PubMedCrossRef
17.
Lobo-Silva D, Carriche GM, Castro AG, Roque S, Saraiva M. Balancing the immune response in the brain: IL-10 and its regulation. J Neuroinflammation. 2016;13(1):297.PubMedPubMedCentralCrossRef
18.
19.
Xin J, Wainwright DA, Mesnard NA, Serpe CJ, Sanders VM, Jones KJ. IL-10 within the CNS is necessary for CD4+ T cells to mediate neuroprotection. Brain Behav Immun. 2011;25(5):820–9.PubMedCrossRef
20.
21.
Chai JG, Bartok I, Chandler P, Vendetti S, Antoniou A, Dyson J, et al. Anergic T cells act as suppressor cells in vitro and in vivo. Eur J Immunol. 1999;29(2):686–92.PubMedCrossRef
22.
Vendetti S, Chai JG, Dyson J, Simpson E, Lombardi G, Lechler R. Anergic T cells inhibit the antigen-presenting function of dendritic cells. J Immunol. 2000;165(3):1175–81.PubMedCrossRef
23.
Dasgupta S, Jana M, Liu X, Pahan K. Myelin basic protein-primed T cells induce nitric oxide synthase in microglial cells. Implications for multiple sclerosis. J Biol Chem. 2002;277(42):39327–33.PubMedCrossRef
24.
Murphy AC, Lalor SJ, Lynch MA, Mills KH. Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis. Brain Behav Immun. 2010;24(4):641–51.PubMedCrossRef
25.
26.
Chen J, Wang W, Li Q. Increased Th1/Th17 responses contribute to low-grade inflammation in age-related macular degeneration. Cell Physiol Biochem. 2017;44(1):357–67.PubMedCrossRef
27.
Olmstead DN, Mesnard-Hoaglin NA, Batka RJ, Haulcomb MM, Miller WM, Jones KJ. Facial nerve axotomy in mice: a model to study motoneuron response to injury. J Vis Exp. 2015;96:e52382.
28.
Villacampa N, Almolda B, Vilella A, Campbell IL, Gonzalez B, Castellano B. Astrocyte-targeted production of IL-10 induces changes in microglial reactivity and reduces motor neuron death after facial nerve axotomy. Glia. 2015;63(7):1166–84.PubMedCrossRef
29.
Huang Z, Meola D, Petitto JM. Dissecting the effects of endogenous brain IL-2 and normal versus autoreactive T lymphocytes on microglial responsiveness and T cell trafficking in response to axonal injury. Neurosci Lett. 2012;526(2):138–43.PubMedPubMedCentralCrossRef
30.
Ha GK, Huang Z, Parikh R, Pastrana M, Petitto JM. Immunodeficiency impairs re-injury induced reversal of neuronal atrophy: relation to T cell subsets and microglia. Exp Neurol. 2007;208(1):92–9.PubMedPubMedCentralCrossRef
31.
Almolda B, Costa M, Montoya M, Gonzalez B, Castellano B. CD4 microglial expression correlates with spontaneous clinical improvement in the acute Lewis rat EAE model. J Neuroimmunol. 2009;209(1-2):65–80.PubMedCrossRef
32.
Kotenko SV, Krause CD, Izotova LS, Pollack BP, Wu W, Pestka S. Identification and functional characterization of a second chain of the interleukin-10 receptor complex. EMBO J. 1997;16(19):5894–903.PubMedPubMedCentralCrossRef
33.
Spencer SD, Di Marco F, Hooley J, Pitts-Meek S, Bauer M, Ryan AM, et al. The orphan receptor CRF2-4 is an essential subunit of the interleukin 10 receptor. J Exp Med. 1998;187(4):571–8.PubMedPubMedCentralCrossRef
34.
Haulcomb MM, Mesnard NA, Batka RJ, Alexander TD, Sanders VM, Jones KJ. Axotomy-induced target disconnection promotes an additional death mechanism involved in motoneuron degeneration in amyotrophic lateral sclerosis transgenic mice. J Comp Neurol. 2014;522(10):2349–76.PubMedPubMedCentralCrossRef
35.
Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74(4):691–705.PubMedPubMedCentralCrossRef
36.
Sabha M Jr, Emirandetti A, Cullheim S, De Oliveira AL. MHC I expression and synaptic plasticity in different mice strains after axotomy. Synapse. 2008;62(2):137–48.PubMedCrossRef
37.
Oliveira AL, Thams S, Lidman O, Piehl F, Hokfelt T, Karre K, et al. A role for MHC class I molecules in synaptic plasticity and regeneration of neurons after axotomy. Proc Natl Acad Sci U S A. 2004;101(51):17843–8.PubMedPubMedCentralCrossRef
38.
Krukowski K, Eijkelkamp N, Laumet G, Hack CE, Li Y, Dougherty PM, et al. CD8+ T Cells and endogenous IL-10 are required for resolution of chemotherapy-induced neuropathic pain. J Neurosci. 2016;36(43):11074–83.PubMedPubMedCentralCrossRef
39.
Chen H, Lin W, Zhang Y, Lin L, Chen J, Zeng Y, et al. IL-10 Promotes neurite outgrowth and synapse formation in cultured cortical neurons after the oxygen-glucose deprivation via JAK1/STAT3 pathway. Sci Rep. 2016;6:30459.PubMedPubMedCentralCrossRef
40.
Fouda AY, Kozak A, Alhusban A, Switzer JA, Fagan SC. Anti-inflammatory IL-10 is upregulated in both hemispheres after experimental ischemic stroke: hypertension blunts the response. Exp Transl Stroke Med. 2013;5(1):12.PubMedPubMedCentralCrossRef
41.
42.
43.
Schandene L, Alonso-Vega C, Willems F, Gerard C, Delvaux A, Velu T, et al. B7/CD28-dependent IL-5 production by human resting T cells is inhibited by IL-10. J Immunol. 1994;152(9):4368–74.PubMed
44.
Akdis CA, Joss A, Akdis M, Faith A, Blaser K. A molecular basis for T cell suppression by IL-10: CD28-associated IL-10 receptor inhibits CD28 tyrosine phosphorylation and phosphatidylinositol 3-kinase binding. FASEB J. 2000;14(12):1666–8.PubMedCrossRef
45.
Joss A, Akdis M, Faith A, Blaser K, Akdis CA. IL-10 directly acts on T cells by specifically altering the CD28 co-stimulation pathway. Eur J Immunol. 2000;30(6):1683–90.PubMedCrossRef
46.
Taylor A, Verhagen J, Blaser K, Akdis M, Akdis CA. Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: the role of T regulatory cells. Immunology. 2006;117(4):433–42.PubMedPubMedCentralCrossRef
47.
48.
Ma SF, Chen YJ, Zhang JX, Shen L, Wang R, Zhou JS, et al. Adoptive transfer of M2 macrophages promotes locomotor recovery in adult rats after spinal cord injury. Brain Behav Immun. 2015;45:157–70.PubMedCrossRef
49.
Zhang XM, Lund H, Mia S, Parsa R, Harris RA. Adoptive transfer of cytokine-induced immunomodulatory adult microglia attenuates experimental autoimmune encephalomyelitis in DBA/1 mice. Glia. 2014;62(5):804–17.PubMedPubMedCentralCrossRef
50.
Steinbrink K, Wolfl M, Jonuleit H, Knop J, Enk AH. Induction of tolerance by IL-10-treated dendritic cells. J Immunol. 1997;159(10):4772–80.PubMed
51.
Tierney JB, Kharkrang M, La Flamme AC. Type II-activated macrophages suppress the development of experimental autoimmune encephalomyelitis. Immunol Cell Biol. 2009;87(3):235–40.PubMedCrossRef
52.
Hayes GM, Woodroofe MN, Cuzner ML. Microglia are the major cell type expressing MHC class II in human white matter. J Neurol Sci. 1987;80(1):25–37.PubMedCrossRef
53.
De Simone R, Giampaolo A, Giometto B, Gallo P, Levi G, Peschle C, et al. The costimulatory molecule B7 is expressed on human microglia in culture and in multiple sclerosis acute lesions. J Neuropathol Exp Neurol. 1995;54(2):175–87.PubMedCrossRef
54.
Ponomarev ED, Shriver LP, Dittel BN. CD40 expression by microglial cells is required for their completion of a two-step activation process during central nervous system autoimmune inflammation. J Immunol. 2006;176(3):1402–10.PubMedCrossRef
55.
Tooyama I, Kimura H, Akiyama H, McGeer PL. Reactive microglia express class I and class II major histocompatibility complex antigens in Alzheimer's disease. Brain Res. 1990;523(2):273–80.PubMedCrossRef
56.
Graeber MB, Streit WJ, Kreutzberg GW. Axotomy of the rat facial nerve leads to increased CR3 complement receptor expression by activated microglial cells. J Neurosci Res. 1988;21(1):18–24.PubMedCrossRef
57.
Berg A, Zelano J, Thams S, Cullheim S. The extent of synaptic stripping of motoneurons after axotomy is not correlated to activation of surrounding glia or downregulation of postsynaptic adhesion molecules. PLoS One. 2013;8(3):e59647.PubMedPubMedCentralCrossRef
58.
Mattsson P, Morgan BP, Svensson M. Complement activation and CD59 expression in the motor facial nucleus following intracranial transection of the facial nerve in the adult rat. J Neuroimmunol. 1998;91(1-2):180–9.PubMedCrossRef
59.
Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352(6286):712–6.PubMedPubMedCentralCrossRef
60.
Heurich B, El Idrissi NB, Donev RM, Petri S, Claus P, Neal J, et al. Complement upregulation and activation on motor neurons and neuromuscular junction in the SOD1 G93A mouse model of familial amyotrophic lateral sclerosis. J Neuroimmunol. 2011;235(1-2):104–9.PubMedCrossRef
61.
Sta M, Sylva-Steenland RM, Casula M, de Jong JM, Troost D, Aronica E, et al. Innate and adaptive immunity in amyotrophic lateral sclerosis: evidence of complement activation. Neurobiol Dis. 2011;42(3):211–20.PubMedCrossRef
62.
Chiu IM, Phatnani H, Kuligowski M, Tapia JC, Carrasco MA, Zhang M, et al. Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice. Proc Natl Acad Sci U S A. 2009;106(49):20960–5.PubMedPubMedCentralCrossRef
63.
Shen Y, Li R, McGeer EG, McGeer PL. Neuronal expression of mRNAs for complement proteins of the classical pathway in Alzheimer brain. Brain Res. 1997;769(2):391–5.PubMedCrossRef
64.
Kawamata T, Akiyama H, Yamada T, McGeer PL. Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am J Pathol. 1992;140(3):691–707.PubMedPubMedCentral
65.
Forsyth JK, Lewis DA. Mapping the consequences of impaired synaptic plasticity in schizophrenia through development: an integrative model for diverse clinical features. Trends Cogn Sci. 2017;21(10):760–78.PubMedPubMedCentralCrossRef
66.
Fluiter K, Opperhuizen AL, Morgan BP, Baas F, Ramaglia V. Inhibition of the membrane attack complex of the complement system reduces secondary neuroaxonal loss and promotes neurologic recovery after traumatic brain injury in mice. J Immunol. 2014;192(5):2339–48.PubMedCrossRef
67.
Lopez-Redondo F, Nakajima K, Honda S, Kohsaka S. Glutamate transporter GLT-1 is highly expressed in activated microglia following facial nerve axotomy. Brain Res Mol Brain Res. 2000;76(2):429–35.PubMedCrossRef
68.
Kamanaka M, Huber S, Zenewicz LA, Gagliani N, Rathinam C, O'Connor W Jr, et al. Memory/effector (CD45RB(lo)) CD4 T cells are controlled directly by IL-10 and cause IL-22-dependent intestinal pathology. J Exp Med. 2011;208(5):1027–40.PubMedPubMedCentralCrossRef
69.
Shouval DS, Konnikova L, Griffith AE, Wall SM, Biswas A, Werner L, et al. Enhanced TH17 responses in patients with IL10 receptor deficiency and infantile-onset IBD. Inflamm Bowel Dis. 2017;23(11):1950–61.PubMedCrossRef
70.
Martinez-Forero I, Garcia-Munoz R, Martinez-Pasamar S, Inoges S, Lopez-Diaz de Cerio A, Palacios R, et al. IL-10 suppressor activity and ex vivo Tr1 cell function are impaired in multiple sclerosis. Eur J Immunol. 2008;38(2):576–86.PubMedCrossRef
71.
Cui HD, Qi ZM, Yang LL, Qi L, Zhang N, Zhang XL, et al. Interleukin-10 receptor expression and signalling were down-regulated in CD4(+) T cells of lupus nephritis patients. Clin Exp Immunol. 2011;165(2):163–71.PubMedPubMedCentralCrossRef
72.
Jones TB, Ankeny DP, Guan Z, McGaughy V, Fisher LC, Basso DM, et al. Passive or active immunization with myelin basic protein impairs neurological function and exacerbates neuropathology after spinal cord injury in rats. J Neurosci. 2004;24(15):3752–61.PubMedPubMedCentralCrossRef
73.
Ankeny DP, Popovich PG. Central nervous system and non-central nervous system antigen vaccines exacerbate neuropathology caused by nerve injury. Eur J Neurosci. 2007;25(7):2053–64.PubMedCrossRef
74.
Ford AL, Foulcher E, Lemckert FA, Sedgwick JD. Microglia induce CD4 T lymphocyte final effector function and death. J Exp Med. 1996;184(5):1737–45.PubMedCrossRef
75.
DeBoy CA, Byram SC, Serpe CJ, Wisuri D, Sanders VM, Jones KJ. CD4 + CD25+ regulatory T cells and CD1-restricted NKT cells do not mediate facial motoneuron survival after axotomy. J Neuroimmunol. 2006;176(1-2):34–8.PubMedCrossRef
76.
Zhou L, Chong MM, Littman DR. Plasticity of CD4+ T cell lineage differentiation. Immunity. 2009;30(5):646–55.PubMedCrossRef
Metadata
Title
CD4+ T cell expression of the IL-10 receptor is necessary for facial motoneuron survival after axotomy
Authors
Elizabeth M. Runge
Abhirami K. Iyer
Deborah O. Setter
Felicia M. Kennedy
Virginia M. Sanders
Kathryn J. Jones
Publication date
01-12-2020
Publisher
BioMed Central
Keyword
Nerve Injury
Published in
Journal of Neuroinflammation / Issue 1/2020
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-020-01772-x

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