Neruons; regulators of CNS inflammation

Abstract: Neurons have been neglected as cells with major immune regulatory function. Here, we present novel data demonstrating that neurons are highly immune competent and play crucial role in regulation of T cell response and CNS inflammation. Neurons induce proliferation of activated CD4+T cells via B7-CD28 and TGF-?1-TGF-?R signaling pathways with amplification of TCR signaling and increased phosphorylated ZAP-70, IL-2 and IL-9. Neuron-T cell interaction results in conversion of encephalitogenic T cells to CD25+TGF-?1+CTLA-4+ Tregulatory cells which suppress T cells proliferation and inhibit EAE. The suppression is dependent on CTLA-4 but not TGF-?1. However, autocrine action of TGF-?1 is important for proliferative arrest of Treg cells. Early enrichment of membrane-bound TGF-?1+CD4+ T cells in CNS of EAE mice proceeded by intracellular production of TGF-?1 and generation of CD25+TGF-?1+CTLA-4+ Treg cells, these cells in turn prevent EAE. This reveals the physiological importance of the generation of Treg cells in CNS upon interaction with neurons with a key role to down-regulate CNS inflammation. In addition, neurons upregulate PD-L1 upon interaction with encephalitogenic T cells, which in turns leads to generation of a CD4highPD-L1high T cell population. Mice deficient in IFN-? are defective in upregulation of this pathway. This defect is associated with absence of PD-L1 upregulation on motor neurons in the CNS, defective in situ generation of CD4highPD-L1high T cells as well as augmented EAE. Hence, motor neurons in addition to their capacity to generate Treg cells from committed encephalitogic T cells, are crucial in regulation of CNS inflammation through a secondary mechanism leading to induction of cell cycle arrested of encephalitogenic T cells. CNS is exceptionally sensitive to inflammation-caused damage since post mitotic neurons are incapable of regeneration and loss of neurons is associated with loss of vital functions imperative for survival of organism. Hence, neurons are equipped with delicate regulatory properties to limit inflammation of the CNS.