Bringing IL-2 down to earth

In this issue of Blood, Bandyopadhyay and colleagues identify Ikaros as promoting epigenetic changes at the Il2 locus under tolerizing conditions.

In Greek mythology, Ikaros' overexuberance spurs him to fly too close to the sun leading to his demise (figure). Similarly, an important feature of both innate and adaptive immunity is to prevent overexuberant responses and protect the host from developing horror autotoxicus. Through negative selection, the thymus plays an important role in maintaining tolerance. Even so, it is clear that peripheral immunoregulation is necessary to maintain the balance between protective immunity and preventing autoimmunity. One such mechanism is T-cell anergy. When TCR engagement occurs in the absence of costimulation, not only do the T cells fail to become fully activated but they fail to respond upon subsequent rechallenge under fully activating conditions.¹  T-cell anergy has been implicated in playing a role in preventing autoimmune diseases, preventing graft rejection, and leading to the ability of tumors to evade T-cell–mediated destruction. In this current issue of Blood, Bandyopadhyay and colleagues identify the transcription factor Ikaros as playing a role in promoting T-cell anergy.

Ikaros was the first member of a family of zinc finger DNA-binding proteins, which play an important role in regulating cells of hematopoietic origin.²  Specifically, Ikaros is integral in determining lymphocyte cell fate from pluripotent precursors. Functionally, Ikaros acts as a transcriptional repressor by recruiting to the promoter chromatin remodeling complexes containing histone deacetylases. Bandyopadhyay and colleagues were interested in the potential role of epigenetic changes as a means of inhibiting IL-2 expression in T-cell anergy. In the current report, the authors demonstrate that sustained calcium signaling leading to T-cell anergy induces histone deacetylation at the Il2 locus. In an effort to understand the mechanism accounting for this finding, they observed that Ikaros was one of the genes up-regulated during the induction of T-cell anergy. Indeed, their data demonstrate that Ikaros is recruited to the IL-2 promoter during anergy induction and overexpression of Ikaros inhibits IL-2 production. Of importance, this inhibition is mitigated in the presence of a HDAC inhibitor, implicating the ability of Ikaros to recruit histone deacetylases as the mechanism of inhibition. Furthermore, by knocking down Ikaros with siRNA, Bandyopadhyay et al were able to prevent the deacetylation of the Il2 promoter, resulting in increased IL-2 production upon rechallenge.

While it has been about 20 years since the first description of T-cell clonal anergy, it is only recently that the mechanisms accounting for this form of T-cell tolerance have been elucidated. The E3 ligases Cbl-b and Grail have been implicated in inhibiting PLC-γ–mediated signaling that is seen early after anergy induction.¹  Rap1 activation and diacylglycerol kinase-alpha play a role in the inhibition of the ras-MAP kinase pathway that is characteristic of anergic T cells.^3,4  However, in spite of these signaling defects, the production of certain cytokines and chemokines (MIP1-α, for example) remains intact in anergic cells.¹  Such observations suggest a role for a promoter-specific inhibitory mechanism. Along these lines, the binding of CREB/CREM and Smad3/4 inhibitory complexes as well as methylation have been demonstrated in anergy at the Il2 promoter.^5-7  These new observations demonstrating Ikaros-mediated epigenetic changes not only enhance our understanding of the functional specificity seen in anergy but also explain in part the long-term stability of the anergic phenotype.