A current paradigm has ICOS participating in TH2 costimulation. New data indicates ICOS regulates not only TH2 cells, but also TH1s. have reduced amounts of TH2 immunoglobulin isotypes and produce little IL-4 after secondary stimulation7–9. Thus, a paradigm has developed in which ICOS provides a unique role in TH2 costimulation. Hancock and colleagues provide evidence that challenges this paradigm; they show that blockade of ICOS signaling leads to increased heart allograft acceptance and reduced evidence of chronic rejection2. Acute allograft rejection is not TH2-mediated, but is a TH1-dependent inflammatory response that leads to the destruction of graft tissue2. They show clearly that anti-ICOS therapy alone, or in combination with blockade of CD40 ligand (CD40L, also known as CD154), has a profound effect on the TH1 response. It markedly decreases graft infiltration by both CD4+ and CD8+ T cell subsets; it also suppresses upregulation of the proinflammatory cytokine interferon-γ (IFN-γ) in the intragraft while markedly down-regulating chemokines critical for allograft responses. In light of these results, a re-examination of the role of ICOS as a regulator of T cell differentiation is warranted.

Although in the original studies ICOS-mediated costimulation augmented TH2 cytokine secretion, the production of IFN-γ and tumor necrosis factor-α (TNF-α) by costimulated T cells also increased3. Under certain circumstances, ICOS costimulation resulted in increased IL-2 production10. ICOS blockade of T cell receptor (TCR)-transgenic encephalitogenic T cells during in vitro expansion can prevent the TH1-mediated disease, experimental encephalomyelitis (EAE), in normal recipient mice11; in addition, treatment with B7RP-1–Fc protein can augment TH1, as well as TH2, responses in mice12. Therefore, ICOS almost certainly plays a critical role in the differentiation and effector function of both TH1 and TH2 cell types. If ICOS regulates all T cell types, how is it