Gene Regulation and Chromatin Remodeling by IL-12 and Type I IFN in Programming for CD8 T Cell Effector Function and Memory

Abstract

A third signal that can be provided by IL-12 or type I IFN is required for differentiation of naive CD8 T cells responding to Ag and costimulation. The cytokines program development of function and memory within 3 days of initial stimulation, and we show here that programming involves regulation of a common set of ∼355 genes including T-bet and eomesodermin. Much of the gene regulation program is initiated in response to Ag and costimulation within 24 h but is then extinguished unless a cytokine signal is available. Histone deacetylase inhibitors mimic the effects of IL-12 or type I IFN signaling, indicating that the cytokines relieve repression and allow continued gene expression by promoting increased histone acetylation. In support of this, increased association of acetylated histones with the promoter loci of granzyme B and eomesodermin is shown to occur in response to IL-12, IFN-α, or histone deacetylase inhibitors. Thus, IL-12 and IFN-α/β enforce in common a complex gene regulation program that involves, at least in part, chromatin remodeling to allow sustained expression of a large number of genes critical for CD8 T cell function and memory.

Type I Interferon Signaling Enhances CD8+T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection

“…This model is supported in vivo during LCMV infection, wherein a loss of intrinsic CD8 ϩ type I IFN signaling results in a severe (Ͼ99%) reduction in LCMVspecific CD8 ϩ T cell expansion and memory pool formation (10). Direct type I IFN signaling on CD8 ϩ T cells also upregulates effector and cytotoxicity-associated transcripts, which include granzyme B, IFN-␥, and FasL (21). Therefore, we predicted that intrinsic type I IFN signaling on CD8 ϩ T cells would mediate effector function and memory differentiation during MHV68 infection.…”

“…Type I IFN signaling has been shown to support CD8 ϩ T cell effector capabilities, including cytokine production (11,21). We assessed the role of type I IFNs in MHV68-directed CD8…”

Redirected T-Cell Killing of Solid Cancers Targeted with an Anti-CD3/Trop-2–Bispecific Antibody Is Enhanced in Combination with Interferon-α

“…IFNa has a pleiotropic influence on immune responses through effects on myeloid cells, NK cells, DCs, B cells, and T cells, and influences the production of numerous other cytokines, including IFNg, TNFa, IL1, IL6, IL12, IL15, and IL18 (23). Several reports identify CD8 þ T cells as direct targets of IFNa, affecting their IFNg production, survival, activation, clonal expansion, and memory differentiation (24)(25)(26)(27)(28)(29)(30)(31). IFNa provides a strong and direct signal to human CD8 þ T cells, thereby resulting in upregulation of critical genes for cytotoxic T-cell activity, and is absolutely critical in the case of human-naive CD8 þ T cells for effector function acquisition (26).…”

IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization

“…Particular cytokine receptors, such as the type I interferon receptor and IL-12R, execute targeted up-regulation of key transcription factors necessary for supporting T-cell expansion and the initiation of both T-cell effector and memory-fate programs (6,7). Encounters that produce longstanding cellular immunity induce a balanced cytokine milieu, using both stimulatory (STAT1) and suppressive (STAT3) signaling pathways.…”