Haptoglobin directly affects T cells and suppresses T helper cell type 2 cytokine release

Summary T helper cell type 1 (Th1) and type 2 (Th2) immune responses are characterized by a different pattern of cytokine expression following T‐cell activation. Alterations of the ratio of Th1 to Th2 cells are important determinants of susceptibility to viral and parasitic infections, allergies, anti‐tumour responses, and autoimmunity. In this work we bring new evidence for an effect of haptoglobin (Hp), a positive acute‐phase protein, on T‐lymphocyte functions. We show that Hp specifically interacts with both resting and activated CD4+ and CD8+ T cells. This specific binding results in a strong suppression of induced T‐cell proliferation. In addition, Hp exhibits a strong in vitro inhibitory effect on Th2 cytokine release, while the production of interferon‐γ (IFN‐γ) and interleukin‐2 (IL‐2) is only slightly inhibited at high Hp doses. As a result, the presence of Hp promotes Th1 activation over Th2 activation in vivo as evidenced in Hp‐deficient mice. Anti‐CD3 monoclonal antibody injection indeed resulted in predominant IL‐4 production in Hp−/− mice, in contrast to predominant IFN‐γ production in Hp+/+ mice. We conclude that Hp plays a modulating role on the Th1/Th2 balance by promoting a dominant Th1 cellular response. This points to a role of acute‐phase proteins in balancing immune responses.