Timing and tuning of CD27–CD70 interactions: the impact of signal strength in setting the balance between adaptive responses and immunopathology

Abstract

After binding its natural ligand cluster of differentiation 70 (CD70), CD27, a tumor necrosis factor receptor (TNFR)-associated factor-binding member of the TNFR family, regulates cellular activity in subsets of T, B, and natural killer cells as well as hematopoietic progenitor cells. In normal immune responses, CD27 signaling appears to be limited predominantly by the restricted expression of CD70, which is only transiently expressed by cells of the immune system upon activation. Studies performed in CD27-deficient and CD70-transgenic mice have defined a non-redundant role of this receptor-ligand pair in shaping adaptive T-cell responses. Moreover, adjuvant properties of CD70 have been exploited for the design of anti-cancer vaccines. However, continuous CD27-CD70 interactions may cause immune dysregulation and immunopathology in conditions of chronic immune activation such as during persistent virus infection and autoimmune disease. We conclude that optimal tuning of CD27-CD70 interaction is crucial for the regulation of the cellular immune response. We provide a detailed comparison of costimulation through CD27 with its closely related family members 4-1BB (CD137), CD30, herpes virus entry mediator, OX40 (CD134), and glucocorticoid-induced TNFR family-related gene, and we argue that these receptors do not have a unique function per se but that rather the timing, context, and intensity of these costimulatory signals determine the functional consequence of their activity.

CD70-Driven Costimulation Induces Survival or Fas-Mediated Apoptosis of T Cells Depending on Antigenic Load

“…The expression of CD70 is tightly regulated and only transiently present on dendritic cells, B cells, and T cells upon activation, which ensures that signaling through CD27 is limited during times of infection or inflammation (16,17). CD27 enhances T cell responses through multiple mechanisms that include induction of autocrine IL-2 production and shifting the balance of pro-and antiapoptotic molecules toward a prosurvival state (18)(19)(20).…”

Heterodimer‐specific TLR2 stimulation results in divergent functional outcomes in B‐cell precursor acute lymphoblastic leukemia

“…While induction of cell death often depends on the balance between proapoptotic and prosurvival signals [68], the exact signaling networks that induce cell survival or cell death after engagement of TLRs are not yet completely understood [69]. There is increasing evidence that the strength, timing, and duration of TLR signaling can significantly modulate downstream outcomes [70], just as previously observed for T-cell receptor signaling [71,72], and more recently for B-cell receptor signaling [73]. Our study suggests that the distinct activation kinetics of NF-κB and PI3K after stimulation with Pam 3 CSK 4 skew ALL cells toward a proapoptotic signaling cascade, while the rapid activation of both NF-κB and PI3K by TLR2/6 ligand Pam 2 CSK 4 potentially protects ALL cells against proapoptotic signals.…”

“…While both heterodimer-specific ligands significantly upregulated CD40 expression in ALL cells, only the TLR2/1 ligand was able to induce cell death by triggering Caspase-8-mediated apoptosis. The contrasting ability to cause direct tumor cell death may significantly alter the overall anti-tumor effects of TLR2 heterodimers and may [71,72], and more recently for B-cell receptor signaling [73]. Our study suggests that the distinct activation kinetics of NF-κB and PI3K after stimulation with Pam 3 CSK 4 skew ALL cells toward a proapoptotic signaling cascade, while the rapid activation of both NF-κB and PI3K by TLR2/6 ligand Pam 2 CSK 4 potentially protects ALL cells against proapoptotic signals.…”

Inflammation in the CNS: Advancing the Field Using Intravital Imaging

“…Monaco et al revealed corresponding clinical evidence of depressed TRP levels in both serum and CSF of MS patients (69). A subsequent study has yielded conflicting results to these findings, however, a negative correlation between neopterin, a marker of macrophage activity, and TRP levels in the CSF was observed, reflecting IFN-γ-induced macrophage induction and IDO-1 activation, respectively (120). Although an additional clinical study this year found an increase in IDO-1 activation via QUIN/KYN ratios in MS patients compared with control, there were no significant differences in kynurenine metabolite levels between MS and other neuroinflammatory disorders.…”

“…Reports have documented the presence of reticular fiber-like structures that develop in the inflamed CNS. These structures, absent in the steady-state CNS, generate a SHG signal and are observed deep within the cortex, discrete from both the vasculature and the meninges (79,120). While their molecular and cellular constituency remains unknown, the reticular fibers appear to provide a scaffold for T cell migration within the parenchyma.…”