Inducible costimulator (ICOS) blockade inhibits accumulation of polyfunctional T helper 1/T helper 17 cells and mitigates autoimmune arthritis

Abstract

Objectives 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 γ or tumour necrosis factor α 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.

Ameliorated course of glucose-6-phosphate isomerase (G6PI)-induced arthritis in IFN-γ receptor knockout mice exposes an arthritis-promoting role of IFN-γ

“…skin reaction upon challenge with G6PI) and G6PI-specific immunoglobulin levels in serum. Given the documented importance of CD4 þ Th cells in G6PI-induced arthritis [19,22,37], the strong reduction of the Th cellular response of IFN-gR KO mice at this early time point may to a large extent account for mitigated arthritis severity in these mice. However, lower numbers of B cells and lower levels of anti-G6PI-immunoglobulins may be equally important since both have been shown to be involved in the pathogenesis of G6PI-induced arthritis [21,25].…”

The Role of Metalloproteinase ADAM17 in Regulating ICOS Ligand–Mediated Humoral Immune Responses

“…In contrast to the HK 5.3 clone, which blocks the interaction of ICOSL with ICOS, clone MIL-666 is a non-blocking Ab, because staining with this Ab is only minimally affected by the presence of the soluble ICOS-Ig chimera (Ref. 31 and data not shown). To avoid competition for a binding site, the clone MIL-666 Ab was used for ICOSL staining when the leukocytes were incubated with L cells and L-ICOS cells.…”

Lack of IL-4 receptor expression on T helper cells reduces T helper 2 cell polyfunctionality and confers resistance in allergic bronchopulmonary mycosis

“…42,43 Thus, ex vivo re-stimulation of isolated pulmonary leukocytes with cryptococcal antigen was done and intracellular cytokine expression was selectively analyzed in CD4 + CD154 + lung lymphocytes. In pulmonary leukocytes of infected Lck Cre IL-4R − / lox and IL-4R − / lox mice, we found similar proportions of antigen-specific Th cells (i.e., CD4 + CD154 + cells) ( Figure 4b ) with equal absolute numbers of lung Th cells (median 4.3 × 10 5 Th cells / lung for Lck Cre IL-4R − / lox and IL-4R − / lox mice).…”