Inducible costimulator (ICOS) blockade inhibits accumulation of polyfunctional T helper 1/T helper 17 cells and mitigates autoimmune arthritis.
OBJECTIVE
Inducible costimulator (ICOS) and its ligand (ICOSL) regulate T and B cell responses. Glucose-6-phosphate isomerase (G6PI)-induced arthritis requires T and B lymphocytes. It was hypothesised that blocking ICOS/ICOSL interactions ameliorates G6PI-induced arthritis and reduces G6PI-specific B and T lymphocyte responses.


METHODS
DBA/1 mice were injected with a blocking, non-depleting anti-ICOSL monoclonal antibodies (mAbs) during the induction or effector phase of G6PI-induced arthritis. G6PI-specific antibody responses were measured by ELISA. G6PI-specific T helper (Th) cell responses were assayed by polychromatic flow cytometry.


RESULTS
Transient blockade of ICOS/ICOSL interactions profoundly reduced the severity of G6PI-induced arthritis. ELISA and proliferation assays showed no clear ex vivo correlates of protection. Polychromatic flow cytometry revealed two major findings: the absolute number of G6PI-specific Th cells was markedly diminished in secondary lymphatic organs from mice with blocked ICOS/ICOSL interactions. Within the pool of G6PI-specific Th cells the frequency of interleukin 17 (IL17), interferon gamma or tumour necrosis factor alpha producers or polyfunctional Th cells (expressing two or more of these cytokines) was higher in treated than in control mice.


CONCLUSIONS
ICOS costimulation is not mandatory for the differentiation of Th1 or Th17 cells. Instead, the lack of ICOS costimulation results in reduced survival of G6PI-specific Th cells irrespective of their functional differentiation. This study demonstrates that a thorough examination of the quantity and the quality of antigen-specific immune responses is useful to determine ex vivo correlates of efficacy for immunomodulating treatments.
Frey
Oliver
O
Institut für Immunologie, Universitätsklinikum Jena, Jena 07743, Germany.
Meisel
Juliane
J
Hutloff
Andreas
A
Bonhagen
Kerstin
K
Bruns
Lisa
L
Kroczek
Richard A
RA
Morawietz
Lars
L
Kamradt
Thomas
T
D000818:Animals; D019138:Antibodies, Blocking / Q000627:therapeutic use*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D001169:Arthritis, Experimental / Q000276:immunology / Q000517:prevention & control*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000517:prevention & control*; D001327:Autoimmune Diseases / Q000276:immunology / Q000517:prevention & control; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D019298:Glucose-6-Phosphate / Q000276:immunology; D007136:Immunoglobulins / Q000096:biosynthesis; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D020381:Interleukin-17 / Q000032:analysis; D008024:Ligands; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D008811:Mice, Inbred DBA; D011506:Proteins / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology
D019138:Antibodies, Blocking; D000945:Antigens, Differentiation, T-Lymphocyte; D016207:Cytokines; C556694:Icos protein, mouse; C400230:Icosl protein, mouse; D007136:Immunoglobulins; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D020381:Interleukin-17; D008024:Ligands; D011506:Proteins; D019298:Glucose-6-Phosphate