Pi3-Kinase P110 Alpha Deficiency Modulates T Cell Homeostasis And Function And Attenuates Experimental Allergic Encephalitis In Mature Mice

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 p110 alpha catalytic subunits in EAE has been analyzed using a model of Cre/flox mediated T cell specific deletion of p110 alpha catalytic chain (p110 alpha Delta T). Comparison of two month-old (young) and six month-old (mature) p110 alpha Delta T mice and their wild type (WT) counterparts indicated loss of spleen CD4(+) T cells that increased with age, indicating a role of p110 alpha in their homeostasis. In contrast, CD4(+) T regulatory (Treg) cells were enhanced in mature p110 alpha Delta T 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 p110 alpha Delta T mice was analyzed. EAE clinical symptoms and disease scores in six month p110 alpha Delta T mice were significantly lower than those of mature WT, or young WT and p110 alpha Delta T mice. Furthermore, ex vivo antigen activation of lymph node cells from MOG immunized mature p110 alpha Delta T mice induced significantly lower levels of IFN-gamma and IL-17A than young p110 alpha Delta T or young and mature WT mice. Other cytokines including IL-2, IL-10 or TNF-alpha showed no significant differences between p110 alpha Delta T and WT mature mice. Our data show a lower incidence of MOG-induced EAE in mature p110 alpha Delta T mice linked to altered T cell homeostasis and lower secretion of inflammatory cytokines.