GM-CSF-Producing Th Cells in Rats Sensitive and Resistant to Experimental Autoimmune Encephalomyelitis

• Published in: PloS one 2016-11, Vol.11 (11), p.e0166498-e0166498
• Main Authors: Leposavic, Gordana, Vujnovic, Ivana, Arsenovic-Ranin, Nevena, Nacka-Aleksic, Mirjana, Dimitrijevic, Mirjana, Pilipovic, Ivan, Stojic-Vukanic, Zorica, Petrovic, Raisa
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Autoimmune diseases; Biology and Life Sciences; Blood cells; CCR2 protein; CD11b antigen; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Cell differentiation; Cells, Cultured; Cerebrospinal fluid; Chemokines; Colony-stimulating factor; Cytokines; Dendritic cells; Differentiation (biology); Drainage; Encephalomyelitis; Encephalomyelitis, Autoimmune, Experimental - immunology; Experimental allergic encephalomyelitis; Female; Gene expression; Genetically engineered foods; Granulocyte-macrophage colony-stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - immunology; Granulocytes; Helper cells; Immunization; Immunology; Inflammation; Interferon; Interleukin 17; Interleukin 23; Interleukin 6; Interleukin-17 - immunology; Laboratory animals; Leukocyte migration; Lymph nodes; Lymphocytes; Lymphocytes T; Macrophages; Medicine and Health Sciences; Monocyte chemoattractant protein 1; Multiple sclerosis; Nervous system; Pathogenesis; Pharmacy; Physiology; Progeny; Rats; Research and Analysis Methods; RNA; Spinal cord; T cell receptors; T-Lymphocytes, Helper-Inducer - immunology; Th17 Cells - immunology; Vaccines; Virology; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0166498

Given that granulocyte macrophage colony-stimulating factor (GM-CSF) is identified as the key factor to endow auto-reactive Th cells with the potential to induce neuroinflammation in experimental autoimmune encephalomyelitis (EAE) models, the frequency and phenotype of GM-CSF-producing (GM-CSF+) Th cells in draining lymph nodes (dLNs) and spinal cord (SC) of Albino Oxford (AO) and Dark Agouti (DA) rats immunized for EAE were examined. The generation of neuroantigen-specific GM-CSF+ Th lymphocytes was impaired in dLNs of AO rats (relatively resistant to EAE induction) compared with their DA counterparts (susceptible to EAE) reflecting impaired CD4+ lymphocyte proliferation and less supportive of GM-CSF+ Th cell differentiation dLN cytokine microenvironment. Immunophenotyping of GM-CSF+ Th cells showed their phenotypic heterogeneity in both strains and revealed lower frequency of IL-17+IFN-γ+, IL-17+IFN-γ-, and IL-17-IFN-γ+ cells accompanied by higher frequency of IL-17-IFN-γ- cells among them in AO than in DA rats. Compared with DA, in AO rats was also found (i) slightly lower surface density of CCR2 (drives accumulation of highly pathogenic GM-CSF+IFN-γ+ Th17 cells in SC) on GM-CSF+IFN-γ+ Th17 lymphocytes from dLNs, and (ii) diminished CCL2 mRNA expression in SC tissue, suggesting their impaired migration into the SC. Moreover, dLN and SC cytokine environments in AO rats were shown to be less supportive of GM-CSF+IFN-γ+ Th17 cell differentiation (judging by lower expression of mRNAs for IL-1β, IL-6 and IL-23/p19). In accordance with the (i) lower frequency of GM-CSF+ Th cells in dLNs and SC of AO rats and their lower GM-CSF production, and (ii) impaired CCL2 expression in the SC tissue, the proportion of proinflammatory monocytes among peripheral blood cells and their progeny (CD45hi cells) among the SC CD11b+ cells were reduced in AO compared with DA rats. Collectively, the results indicate that the strain specificities in efficacy of several mechanisms controlling (auto)reactive CD4+ lymphocyte expansion/differentiation into the cells with pathogenic phenotype and migration of the latter to the SC contribute to AO rat resistance to EAE.