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

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

doi:10.1186/s12974-020-01772-x

Abstract

BackgroundAfter 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).MethodsImmunohistochemical 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.ResultsCD4+ 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.ConclusionsThese 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.

Highlights

IntroductionFacial motoneuron (FMN) survival depends on an intact CD4+ T cell population and a central source of interleukin-10 (IL-10)
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)
Comparison of cell populations was performed in GraphPad Prism using one-way analysis of variance (ANOVA) followed by Student-Newman-Keuls multiple comparisons with an alpha of 0.05 to determine significance. It is unknown whether the CD4+ T cells responsible for mediating neuroprotection after axotomy are capable of infiltrating into the CNS parenchyma, or alternatively whether they must communicate with CNS resident cells across the blood-brain barrier (BBB)

Summary

Introduction

Facial motoneuron (FMN) survival depends on an intact CD4+ T cell population and a central source of interleukin-10 (IL-10). It has not been determined previously whether CD4+ T cells participate in the central neuroprotective IL-10 cascade after facial nerve axotomy (FNA). In the FNA model of peripheral nerve injury, the neuroprotective capacity of the adaptive immune system is specific to Th2 CD4+ T cells, which are sufficient for rescuing FMN survival when adoptively transferred into immunodeficient RAG-2-/- mice [3, 4]. After peripheral activation and clonal expansion, T cells are attracted to the FMNuc by centrally derived chemokines [7,8,9]. Microglia proliferate in the FMNuc after axotomy [13], phagocytize dead neurons [14], and express MHC class I and II molecules, on which they may present neuronal antigen to infiltrating T cells [15, 16]

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