Abstract
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.
Highlights
Experimental autoimmune encephalomyelitis (EAE) is the most frequently used model system for studying multiple sclerosis (MS) in laboratory animals
Given that, judging by CD40 mean fluorescence intensity (MFI) [51], antigen presenting CD40+CD11b+CD45RA- cells from Albino Oxford (AO) rats exhibited stronger activation than those from Dark Agouti (DA) rats, and that CD4+ T:CD40+CD11b+CD45RA- cell ratio was shifted towards the antigen presenting cells in AO rats (56.1±1.21 in AO rats vs 81.25±5.46 in DA rats), whereas the frequency of CD25 +FoxP3+ cells among CD4+ T lymphocytes was comparable between these two rat strains, the strain-specific differences in CD4+ lymphocyte proliferative capacity may be assumed
In addition to lower generation of neuroantigen-specific CD4+ T lymphocytes in AO rat draining lymph nodes (dLNs), the present study suggests impaired polarization of CD4+ T lymphocytes towards granulocyte macrophage colony-stimulating factor (GM-CSF)+ Th cells, as their frequency was reduced among both PMA/ionomycine- and MBPstimulated CD4+ T lymphocytes from AO compared with DA rats
Summary
Experimental autoimmune encephalomyelitis (EAE) is the most frequently used model system for studying multiple sclerosis (MS) in laboratory animals. It has been clearly proven that CD4+ T lymphocytes are the major driver of the disease when rodents are immunized by CNS antigen(s) in complete Freund’s adjuvant (CFA) [8] This EAE model is used as a prototype for CD4+ T lymphocyte-mediated autoimmune diseases [9]. Adoptive transfer of granulocyte macrophage colony-stimulating factor (GM-CSF) sufficient effector T cells that were deficient in both IFN-γ and IL-17 caused severe EAE commensurate with wild type T cells. Based on these observations, GM-CSF is widely considered to be the signature cytokine of pathogenic effector T cells in EAE, and one of the few cytokines critical for EAE [17,18,19,20]. Considering all the aforementioned, it is understandable that driving factors and mechanisms underlying differentiation of GM-CSF-producing (GM-CSF+) Th lymphocytes and its role in the development of autoimmune diseases are gaining increasing attention
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