Peripheral Injection of Tim-3 Antibody Attenuates VSV Encephalitis by Enhancing MHC-I Presentation

Abstract

Viral encephalitis is the most common cause of encephalitis. It is responsible for high morbidity rates, permanent neurological sequelae, and even high mortality rates. The host immune response plays a critical role in preventing or clearing invading pathogens, especially when effective antiviral treatment is lacking. However, due to blockade of the blood-brain barrier, it remains unclear how peripheral immune cells contribute to the fight against intracerebral viruses. Here, we report that peripheral injection of an antibody against human Tim-3, an immune checkpoint inhibitor widely expressed on immune cells, markedly attenuated vesicular stomatitis virus (VSV) encephalitis, marked by decreased mortality and improved neuroethology in mice. Peripheral injection of Tim-3 antibody enhanced the recruitment of immune cells to the brain, increased the expression of major histocompatibility complex-I (MHC-I) on macrophages, and as a result, promoted the activation of VSV-specific CD8+ T cells. Depletion of macrophages abolished the peripheral injection-mediated protection against VSV encephalitis. Notably, for the first time, we found a novel post-translational modification of MHC-I by Tim-3, wherein, by enhancing the expression of MARCH9, Tim-3 promoted the proteasome-dependent degradation of MHC-I via K48-linked ubiquitination in macrophages. These results provide insights into the immune response against intracranial infections; thus, manipulating the peripheral immune cells with Tim-3 antibody to fight viruses in the brain may have potential applications for combating viral encephalitis.

Tim-3 Relieves Experimental Autoimmune Encephalomyelitis by Suppressing MHC-II

“…Li et al. ( 21 ) also found that Tim-3 blockage increases the expression of MHC-I on macrophages and promotes the activation of VSV-specific CD8+ T cells and also markedly attenuates vesicular stomatitis virus (VSV) encephalitis by decreased mortality and improved neuroethology in mice. In this study, we found that Tim-3 can inhibit the MHC-II expression and antigen presentation to CD4+ T cells, which relieves EAE mouse spinal cord demyelination and improves clinical scores.…”

“…The mice were immunized subcutaneously on the back, and Pertussis toxin (PTX, List Biological Laboratories, 180243A1) was injected intraperitoneally at 0 and 48 h after immunization (500 ng PTX per mouse each time). Groping, twenty C57BL/6J mice were immunized and randomly divided into two groups: anti-Tim-3 antibody ( 21 ) group and control antibody group (10 mg/kg, i.p, every other day). Eight Tim-3-TG mice and eight WT mice were immunized.…”

Viral infection in hematopoietic stem cell transplantation: an International Society for Cell & Gene Therapy Stem Cell Engineering Committee review on the role of cellular therapy in prevention and treatment

“…Current approaches to expand the efficacy of adoptive T-cell therapies for infections in immune-compromised hosts include (i) targeting a wider array of viral and non-viral (e.g., fungal) infections; (ii) generating T cells for adoptive therapy that are resistant to immunosuppressive medications that patients are frequently on and (iii) combination therapy to improve antigen presentation by and/or Tcell recognition of the target [115,116]. Studies have shown that immunosuppressive therapy used in the prevention and treatment of GVHD inhibits T-cell activation.…”