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Background: Development of long-lasting anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) T-cell responses in persons with multiple sclerosis (pwMS) treated with ocrelizumab is questioned. Objective: Investigate antiviral T-cell responses after infection with SARS-CoV-2 in ocrelizumab-treated pwMS. Control groups included ocrelizumab-treated pwMS without SARS-CoV-2 infection, and non-MS individuals with and without SARS-CoV-2 infection. Methods: Peripheral blood mononuclear cells were stimulated with SARS-CoV-2 peptide pools and T-cell reactivity was assessed by ELISPOT for interferon (IFN)-γ detection, and by multiparametric fluorescence-activated cell sorting (FACS) analyses for assessment and characterization of T-cell activation. Results: ELISPOT assay against the spike and the N protein of SARS-CoV-2 displayed specific T-cell reactivity in 28/29 (96%) pwMS treated with ocrelizumab and infected by SARS-CoV-2, similar to infected persons without MS. This reactivity was present 1 year after infection and independent from the time of ocrelizumab infusion. FACS analysis following stimulation with SARS-CoV-2 peptide pools showed the presence of activation-induced markers (AIMs) in both CD4+ and CD8+ T-cell subsets in 96% and 92% of these individuals, respectively. Within naïve AIM+ CD4+ and CD8+ T-cells, we detected T memory stem cells, suggesting the acquisition of long-term memory. Conclusions: B-cell depletion using ocrelizumab does not impair the development of long-lasting anti-SARS-CoV-2 T-cell responses.

The approval of immune checkpoint inhibitors (ICIs) by the Food and Drug Administration (FDA) led to an improvement in the treatment of several types of cancer. The main targets of these drugs are cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein-1/programmed death-ligand 1 pathway (PD-1/PD-L1), which are important inhibitory molecules for the immune system. Besides being generally safer than common chemotherapy, the use of ICIs has been associated with several immune-related adverse effects (irAEs). Although rare, neurological adverse effects are reported within the irAEs in clinical trials, particularly in patients treated with anti-PD-1 antibodies or a combination of both anti-CTLA-4 and PD-1 drugs. The observations obtained from clinical trials suggest that the PD-1 axis may play a remarkable role in the regulation of neuroinflammation. Moreover, numerous studies in preclinical models have demonstrated the involvement of PD-1 in several neurological disorders. However, a comprehensive understanding of these cellular mechanisms remains elusive. Our review aims to summarize the most recent evidence concerning the regulation of neuroinflammation through PD-1/PD-L signaling, focusing on cell populations that are involved in this pathway.