TY - JOUR
T1 - Mouse Homologue of Human HLA-DO Does Not Preempt Autoimmunity but Controls Murine Gammaherpesvirus MHV68
AU - Lee, Jean
AU - Cullum, Emily
AU - Stoltz, Kyle
AU - Bachmann, Niklas
AU - Strong, Zoe
AU - Millick, Danielle D.
AU - Denzin, Lisa K.
AU - Chang, Anthony
AU - Tarakanova, Vera
AU - Chervonsky, Alexander V.
AU - Golovkina, Tatyana
N1 - Publisher Copyright: © 2021 by The American Association of Immunologists, Inc.
PY - 2021/12/15
Y1 - 2021/12/15
N2 - H2-O (human HLA-DO) is a relatively conserved nonclassical MHC class II (MHCII)-like molecule. H2-O interaction with human HLA-DM edits the repertoire of peptides presented to TCRs by MHCII. It was long hypothesized that human HLA-DM inhibition by H2-O provides protection from autoimmunity by preventing binding of the high-affinity self-peptides to MHCII. The available evidence supporting this hypothesis, however, was inconclusive. A possibility still remained that the effect of H2-O deficiency on autoimmunity could be better revealed by using H2-O-deficient mice that were already genetically predisposed to autoimmunity. In this study, we generated and used autoimmunity-prone mouse models for systemic lupus erythematosus and organ-specific autoimmunity (type 1 diabetes and multiple sclerosis) to definitively test whether H2-O prevents autoimmune pathology. Whereas our data failed to support any significance of H2-O in protection from autoimmunity, we found that it was critical for controlling a g-herpesvirus, MHV68. Thus, we propose that H2-O editing of the MHCII peptide repertoire may have evolved as a safeguard against specific highly prevalent viral pathogens.
AB - H2-O (human HLA-DO) is a relatively conserved nonclassical MHC class II (MHCII)-like molecule. H2-O interaction with human HLA-DM edits the repertoire of peptides presented to TCRs by MHCII. It was long hypothesized that human HLA-DM inhibition by H2-O provides protection from autoimmunity by preventing binding of the high-affinity self-peptides to MHCII. The available evidence supporting this hypothesis, however, was inconclusive. A possibility still remained that the effect of H2-O deficiency on autoimmunity could be better revealed by using H2-O-deficient mice that were already genetically predisposed to autoimmunity. In this study, we generated and used autoimmunity-prone mouse models for systemic lupus erythematosus and organ-specific autoimmunity (type 1 diabetes and multiple sclerosis) to definitively test whether H2-O prevents autoimmune pathology. Whereas our data failed to support any significance of H2-O in protection from autoimmunity, we found that it was critical for controlling a g-herpesvirus, MHV68. Thus, we propose that H2-O editing of the MHCII peptide repertoire may have evolved as a safeguard against specific highly prevalent viral pathogens.
UR - https://www.scopus.com/pages/publications/85134177854
UR - https://www.scopus.com/pages/publications/85134177854#tab=citedBy
U2 - 10.4049/jimmunol.2100650
DO - 10.4049/jimmunol.2100650
M3 - Article
C2 - 34810225
SN - 0022-1767
VL - 207
SP - 2944
EP - 2951
JO - Journal of Immunology
JF - Journal of Immunology
IS - 12
ER -