Abstract
Class I phosphoinositide 3-kinases (PI3K) are involved in the development of normal and autoimmune responses, including Experimental Autoimmune Encephalomyelitis (EAE), a mouse model for human multiple sclerosis (MS). Here, the role of the ubiquitously expressed class IA PI3K p110α catalytic subunits in EAE has been analyzed using a model of Cre/flox mediated T cell specific deletion of p110α catalytic chain (p110αΔT). Comparison of two month-old (young) and six month-old (mature) p110αΔT mice and their wild type (WT) counterparts indicated loss of spleen CD4+ T cells that increased with age, indicating a role of p110α in their homeostasis. In contrast, CD4+ T regulatory (Treg) cells were enhanced in mature p110αΔT mice when compared to WT mice. Since Myelin Oligodendrocyte Glycoprotein (MOG) peptide-induced EAE is dependent on, or mediated by CD4+ T cells and CD4+ T cell-derived cytokines and controlled by Treg cells, development of EAE in young and mature WT or p110αΔT mice was analyzed. EAE clinical symptoms and disease scores in six month p110αΔT mice were significantly lower than those of mature WT, or young WT and p110αΔT mice. Furthermore, ex vivo antigen activation of lymph node cells from MOG immunized mature p110αΔT mice induced significantly lower levels of IFN-γ and IL-17A than young p110αΔT or young and mature WT mice. Other cytokines including IL-2, IL-10 or TNF-α showed no significant differences between p110αΔT and WT mature mice. Our data show a lower incidence of MOG-induced EAE in mature p110αΔT mice linked to altered T cell homeostasis and lower secretion of inflammatory cytokines.
Highlights
Our previous data indicated that the percentage of CD4+ T cells was significantly lower in the secondary lymphoid organs of young p110α catalytic chain (p110α∆T) mice [31]
In agreement with our previous data, the percentage of CD4+ T cells was significantly lower in p110α∆T mice than their age-matched wild type (WT) counterparts (Figure 1a); aging lowered the percentage of CD4+ T cells in p110α∆T or WT mice (Figure 1a)
We show here that mice whose T cells lack the PI3-K p110α subunit have a marked
Summary
Experimental autoimmune encephalomyelitis (EAE) is a mouse model for human multiple sclerosis (MS), an inflammatory, progressively disabling disease in which elements of the immune system attack and destroy the myelin sheath covering central nervous system neurons [1]. The participation of an array of different cellular and molecular innate and adaptive immune elements at different sites and times during MS requires the identification of effective therapeutic targets, in primary and secondary progressive MS [2]. The development of EAE-induced by administration of Myelin Oligodendrocyte The participation of an array of different cellular and molecular innate and adaptive immune elements at different sites and times during MS requires the identification of effective therapeutic targets, in primary and secondary progressive MS [2]. 4.0/).
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