The CD27 and CD70 Costimulatory Pathway Inhibits Effector Function of T Helper 17 Cells and Attenuates Associated Autoimmunity

Abstract

T helper 17 (Th17) cells protect against infection but also promote inflammation and autoimmunity. Therefore, the factors that govern Th17 cell differentiation are of special interest. The CD27 and CD70 costimulatory pathway impeded Th17 effector cell differentiation and associated autoimmunity in a mouse model of multiple sclerosis. CD27 or CD70 deficiency exacerbated disease, whereas constitutive CD27 signaling strongly reduced disease incidence and severity. CD27 signaling did not impact master regulators of T helper cell lineage commitment but selectively repressed transcription of the key effector molecules interleukin-17 (IL-17) and the chemokine receptor CCR6 in differentiating Th17 cells. CD27 mediated this repression at least in part via the c-Jun N-terminal kinase (JNK) pathway that restrained IL-17 and CCR6 expression in differentiating Th17 cells. CD27 signaling also resulted in epigenetic silencing of the Il17a gene. Thus, CD27 costimulation via JNK signaling, transcriptional, and epigenetic effects suppresses Th17 effector cell function and associated pathological consequences.

Essentials of Th17 cell commitment and plasticity

“…This finding is consistent with a recent report that CD27 signaling reduced the incidence and severity of disease in an EAE model. 188 Therefore, we hypothesized that despite certain phenotypic features of advanced maturation, considerable multipotency and plasticity demonstrated by Th17 cells indicated that these cells are not terminally differentiated, at least when induced in vitro. Despite their phenotype, Th1 cells might represent a more differentiated subset with less capacity to expand, persist, and eliminate tumors in vivo (Figure 3).…”

Inflammation in the CNS: Advancing the Field Using Intravital Imaging

“…−/− and CD70 −/− , and reduced Th17 in CD70-Tg mice (124). They concluded that this increased Th17 differentiation in CD27…”

“…−/− and CD70 −/− animals were due to increased phosphorylation of the JNK and epigenetic modification at IL-17 locus, suggesting that CD70-CD27 signaling directly controls the Th17 response in CD4 + T cells (124). Interestingly, anti-CD70 antibody-mediated blocking of CD70 prevented EAE in SJL/J mice (121), and over-expression of CD70 on the B cells enhanced EAE (126).…”

“…Th1 effectors mediated inflammation of the parenchyma of the spinal cord, but not the brain, while Th17 effectors supported extensive parenchymal inflammation in the brain, but not the spinal cord (123)(124)(125). Not surprisingly, such differences in positioning result in distinct neurological pathologies (122).…”

“…At disease onset, or during relapses, proinflammatory monocytes migrate to the CNS, where their numbers directly correlate with the severity of EAE symptoms (124)(125)(126) and in turn, with elevated levels of neurotoxic QUIN in the spinal cord (67). This migration might be facilitated by a damaged BBB, one of the earliest clinical findings in MS, thought to play a fundamental role in the development of the disease [see BBB Breakdown and Entry of Immune Cells as a Key Hallmark of Early MS Pathology; Ref.…”