The CD40/CD40 ligand system in linking acute neuroinflammation with chronic progressive demyelination

Abstract

Abstract CD4+ T cells play critical roles in mediating adaptive immunity and developing protective host immunity by eliminating infectious viruses. CD40 Ligand expressed on CD4+ T cells known to interact with its cognate receptor CD40 expressed on monocyte/macrophage/microglia to induce several immune functions during inflammation and host immunity. Our study aimed to delineate a potential CD4+ T cell-microglia nexus at the cellular and molecular level using CD4−/− and CD40L−/− mice. Results showed that the absence of CD40L renders mice highly susceptible to murine-coronavirus-MHV-A59/RSA59 infection due to reduced microglia/macrophage activation and significantly dampened effector CD4+ T recruitment to the CNS at the acute-adaptive bridging phase of neuroinflammation. CD40L deficiency significantly impaired the priming, expansion, and activation of lymphoid cells in the deep cervical lymph nodes. Additionally, both CD4−/− and CD40L−/− mice presented with severe chronic phase demyelination and axonal pathology in the brain and spinal cord which was correlated with prolonged virus persistence. Results from this study provide exciting information about a critical role of CD40L in mediating RSA59 induced activation of CD4+ T cells in the CLN and their consequent infiltration into CNS in addition to affecting the numbers and activation of monocyte/macrophage/microglia during the acute-adaptive transition phase. CD40-CD40L interaction in linking the innate-acute and chronic-adaptive immune responses may suggest a novel target in designing prophylaxis for virus-induced demyelination and axonal degeneration, in contrast to autoimmune suppression, which holds only for autoimmune mechanisms of inflammatory demyelination. This work was supported by a Department of Biotechnology, India, research grant (BT/PR 20922/MED/122/37/2016). We thank the Council of Scientific and Industrial Research (CSIR) India for providing fellowships to F.S. the Ministry of Human Resource Development (MHRD), India for providing fellowship to D.C; and the University Grants Commission (UGC), India, for providing fellowship to M.K.