ICOS Expression by Activated Human Th Cells Is Enhanced by IL-12 and IL-23: Increased ICOS Expression Enhances the Effector Function of Both Th1 and Th2 Cells

Abstract

Previous mouse studies have shown that IL-4 increases the expression of ICOS on activated Th cells, resulting in enhanced ICOS expression on Th2 cells. In this study, we show that ICOS expression on human Th cells is not increased by IL-4, but by IL-12 and by IL-23 instead. Consequently, ICOS expression during IL-12-driven Th1 cell polarization was transiently increased compared with the levels on Th0 cells and IL-4-driven Th2 cells. Addition of IL-12 and/or IL-23 during restimulation increased ICOS expression to the same extent on pre-established Th1, Th2, and Th0 cells, indicating that ICOS levels are not stably imposed by prior polarization. In contrast to the findings in the mouse, IL-4 significantly suppressed the ICOS-enhancing effects of IL-12 and IL-23. The functional consequence of variable ICOS levels was shown in coculture experiments with cells expressing the ICOS-ligand B7-related protein 1 (either transfected Chinese hamster ovary cells or autologous dendritic cells). Ligation of ICOS on 2-day-preactivated effector cells increased their cytokine production to an extent proportional to their ICOS expression levels. As the ICOS-enhancing potentials of IL-12 and IL-23 were maintained for several days after stimulation, both on Th1 and Th2 cells, we propose the concept that local regulation of ICOS expression on activated Th cells by IL-12 and/or IL-23 may provide a powerful means to amplify effector T cell responses in peripheral tissues, independently of the polarized state of the Th cells.

ICOS cooperates with CD28, IL‐2, and IFN‐γ and modulates activation of human naïve CD4+ T cells

“…This possibility is supported by data on ICOS-and B7h-deficient mice showing defective T cell proliferation and cytokine secretion. It is also in line with the findings of Wassink et al [33] that ICOS potentiates cytokine secretion in both Th1-and Th2-oriented cell lines.…”

“…The few data from humans point to a different behavior. For instance, our work in the mouse suggests that IL-4 and ICOS build up a positive feedback loop, in which initial secretion of small amounts of IL-4 induces expression of ICOS, whose triggering then enhances IL-4 secretion [31,32], whereas in humans ICOS expression appears to be up-regulated by IL-12 and IL-23, and is higher in Th1 than in Th2 cells, and ICOS itself appears to play no part in Th1:Th2 polarization [33,34].…”

Impaired Regulatory T-Cell Response and Enhanced Atherosclerosis in the Absence of Inducible Costimulatory Molecule

“…8 However, recent studies show that ICOS is also involved in Th1 differentiation. 31,32 Consistent with this, we saw an increase in both Th1 and Th2 cytokine production by CD4 ϩ T cells isolated from ICOS-deficient hypercholesterolemic mice ex vivo. Therefore, we do not think a change in Th1:Th2 balance explains the effect of ICOS deficiency in the present study.…”

B7RP-1-ICOS Interactions Are Required for Optimal Infection-Induced Expansion of CD4+ Th1 and Th2 Responses

“…In contrast, its contribution to the development of polarized helper T cell subsets has been less clear. There are conflicting reports that place ICOS solely in the differentiation of Th2 cells (5,6,54): those that suggest that it is important in Th1 cells (15,51) and studies that give ICOS a degree of significance in Th1 and Th2 cell generation (4,48,50,52). It has been unclear whether these apparently contradictory findings were simply a reflection of the individual experimental systems being used, or if ICOS was a key receptor involved in dictating polarity of Th cell responses.…”