Down-Regulation of ICOS Ligand by Interaction with ICOS Functions as a Regulatory Mechanism for Immune Responses

Abstract

Although it is well-known that the ICOS-ICOS ligand (ICOSL) costimulatory pathway is important for many immune responses, recent accumulated evidence suggests that dysregulation of this pathway may lead to and/or exaggerate autoimmune responses. ICOS is induced on the cell surface after T cell activation. Similarly, ICOSL is up-regulated on APCs by several mitogenic stimuli. However, the mechanism regulating expression of the ICOS-ICOSL pair, and the significance of controlling their expression for an appropriate immune response, is largely unknown. To gain a better understanding of the importance of fine control of the ICOS-ICOSL costimulatory pathway, we generated ICOS-transgenic (Tg) mice that have high constitutive expression of ICOS in all T cells. Using ICOS-Tg mice, we studied whether in vivo immune responses were affected. Unexpectedly, we first found that ICOS-Tg mice exhibited a phenotype resembling ICOS-deficient mice in their Ag-specific Ab response, such as a defect in class switch recombination. Further examination revealed that ICOSL expression of APCs was significantly suppressed in ICOS-Tg mice. Interestingly, suppression of ICOSL was induced by interaction of ICOSL with ICOS, and it seemed to be regulated at the posttranscriptional level. The suppressive effect of the ICOS-ICOSL interaction overcame the positive effect of CD40 or B cell activation factor of the TNF family (BAFF) stimulation on ICOSL expression. Together, our studies demonstrate a novel mechanism for the regulation of ICOSL expression in vivo and suggest that the ICOS costimulatory pathway is subject to negative feedback regulation by ICOSL down-regulation in response to ICOS expression.

ICOS-Expressing CD4 T Cells Induced via TLR4 in the Nasal Mucosa Are Capable of Inhibiting Experimental Allergic Asthma

“…However, we did not confirm whether the CD4 + ICOS + Foxp3 + or CD4 + ICOS + Foxp3 2 populations mediated this inhibition and whether their recruitment to the lungs was necessary for protection. There is evidence to suggest that either population could be inhibitory, given that ICOS-ICOS ligand (ICOS-L) interaction alone has been shown to induce immunoregulatory negative feedback (60). Consistent with our findings, ICOS + cells inducing T cell anergy without a requirement for IL-10 have been identified in both humans and mice (61,62).…”

Circulating CD40 + and CD86 + B Cell Subsets Demonstrate Opposing Associations With Risk of Stroke

“…50 In accordance, ICOS has been demonstrated to have a critical role as a regulator of various immune responses, and accumulating evidence suggests that a dysregulation of the ICOS-ICOSL costimulatory pathway may lead to exaggerated autoimmune responses. 51,52 The present study demonstrates that high surface expression of ICOSL on CD19 + B cells associates with a proinflammatory cytokine profile. In contrast, we found that high surface expression of HLA-DR on both B cell subsets was associated with less common carotid intima-media thickness, a finding that remains to be further elucidated.…”

Deficiency in TNFRSF13B (TACI) expands T-follicular helper and germinal center B cells via increased ICOS-ligand expression but impairs plasma cell survival

“…However, it is not clear whether TACI actively signals B7H2 down-modulation or sequesters BAFF away from BAFF-R, which signals B7H2 up-regulation. We favor the latter, because we and others have shown that exogenous BAFF can upregulate B7H2 expression on B cells (26,27) (Fig. S4A), and because elevated BAFF levels have been found in the sera of Taci −/− mice (28) and TACI-mutated patients (29).…”