CD8+ T cells specific for cryptic apoptosis-associated epitopes exacerbate experimental autoimmune encephalomyelitis.

Abstract

The autoimmune immunopathology occurring in multiple sclerosis (MS) is sustained by myelin-specific and -nonspecific CD8+ T cells. We have previously shown that, in MS, activated T cells undergoing apoptosis induce a CD8+ T cell response directed against antigens that are unveiled during the apoptotic process, namely caspase-cleaved structural proteins such as non-muscle myosin and vimentin. Here, we have explored in vivo the development and the function of the immune responses to cryptic apoptosis-associated epitopes (AEs) in a well-established mouse model of MS, experimental autoimmune encephalomyelitis (EAE), through a combination of immunization approaches, multiparametric flow cytometry, and functional assays. First, we confirmed that this model recapitulated the main findings observed in MS patients, namely that apoptotic T cells and effector/memory AE-specific CD8+ T cells accumulate in the central nervous system of mice with EAE, positively correlating with disease severity. Interestingly, we found that AE-specific CD8+ T cells were present also in the lymphoid organs of unprimed mice, proliferated under peptide stimulation in vitro, but failed to respond to peptide immunization in vivo, suggesting a physiological control of this response. However, when mice were immunized with AEs along with EAE induction, AE-specific CD8+ T cells with an effector/memory phenotype accumulated in the central nervous system, and the disease severity was exacerbated. In conclusion, we demonstrate that AE-specific autoimmunity may contribute to immunopathology in neuroinflammation.

• Authors: Neda Feizi, Chiara Focaccetti, Ilenia Pacella, Gloria Tucci, Alessandra Rossi, Massimo Costanza, Rosetta Pedotti, John Sidney, Alessandro Sette, Claudia La Rocca, Claudio Procaccini, Giuseppe Matarese, Vincenzo Barnaba, Silvia Piconese
• Journal: Cell death & disease (Cell Death Dis) Vol. 12 Issue 11 Pg. 1026 (10 29 2021) ISSN: 2041-4889 [Electronic] England
• PMID: 34716313 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Epitopes, T-Lymphocyte
• Myelin-Oligodendrocyte Glycoprotein
• Peptide Fragments
• ovalbumin (256-264)
• Ovalbumin

Topics

• Animals
• Apoptosis (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Central Nervous System (immunology)
• Encephalomyelitis, Autoimmune, Experimental (immunology)
• Epitopes, T-Lymphocyte (immunology)
• Female
• Immunization (methods)
• Lymphocyte Activation (immunology)
• Male
• Mice
• Mice, Inbred C57BL
• Multiple Sclerosis (immunology)
• Myelin-Oligodendrocyte Glycoprotein (administration & dosage)
• Ovalbumin (administration & dosage)
• Peptide Fragments (administration & dosage)
• Phenotype
• Severity of Illness Index