Loss of Immune Tolerance Is Controlled by ICOS in Sle1 Mice.
ICOS, a member of the CD28 family, represents a key molecule that regulates adaptive responses to foreign Ags. ICOS is prominently expressed on T follicular helper (TFH) cells, a specialized CD4(+) T cell subset that orchestrates B cell differentiation within the germinal centers and humoral response. However, the contribution of ICOS and TFH cells to autoantibody profiles under pathological conditions has not been thoroughly investigated. We used the Sle1 lupus-prone mouse model to examine the role of ICOS in the expansion and function of pathogenic TFH cells. Genetic deletion of ICOS impacted the expansion of TFH cells in B6.Sle1 mice and inhibited the differentiation of B lymphocytes into plasma cells. The phenotypic changes observed in B6.Sle1-ICOS-knockout mice were also associated with a significant reduction in class-switched IgG, and anti-nucleosomal IgG-secreting B cells compared with B6.Sle1 animals. The level of vascular cell adhesion protein 1, a molecule that was shown to be elevated in patients with SLE and in lupus models, was also increased in an ICOS-dependent manner in Sle1 mice and correlated with autoantibody levels. The elimination of ICOS-expressing CD4(+) T cells in B6.Sle1 mice, using a glyco-engineered anti-ICOS-depleting Ab, resulted in a significant reduction in anti-nucleosomal autoantibodies. Our results indicate that ICOS regulates the ontogeny and homeostasis of B6.Sle1 TFH cells and influences the function of TFH cells during aberrant germinal center B cell responses. Therapies targeting the ICOS signaling pathway may offer new opportunities for the treatment of lupus and other autoimmune diseases.
Department of Respiratory, Inflammation, and Autoimmunity, MedImmune LLC, Gaithersburg, MD 20878; and.
Nanette
0000-0001-5533-6247
N
Mittereder
Department of Respiratory, Inflammation, and Autoimmunity, MedImmune LLC, Gaithersburg, MD 20878; and.
Ellen
E
Kuta
Department of Respiratory, Inflammation, and Autoimmunity, MedImmune LLC, Gaithersburg, MD 20878; and.
Geetha
G
Bhat
Department of Pathology, MedImmune LLC, Gaithersburg, MD 20878.
Karma
0000-0002-9600-1889
K
Dacosta
Department of Pathology, MedImmune LLC, Gaithersburg, MD 20878.
Lily I
LI
Cheng
Department of Respiratory, Inflammation, and Autoimmunity, MedImmune LLC, Gaithersburg, MD 20878; and.
Ronald
0000-0003-1702-7739
R
Herbst
Department of Respiratory, Inflammation, and Autoimmunity, MedImmune LLC, Gaithersburg, MD 20878; and carlessog@medimmune.com.
Gianluca
G
Carlesso
D019264:Adoptive Transfer; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007150:Immunohistochemistry; D060889:Inducible T-Cell Co-Stimulator Protein / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology
D018398:Homeodomain Proteins; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; C481797:Pbx1 protein, mouse; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D014157:Transcription Factors