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To obtain a molecular definition of regulatory T (Treg) cell identity, we performed proteomics and transcriptomics on various populations of human regulatory and conventional CD4+ T (Tconv) cells. A protein expression signature was identified that defines all Treg cells, and another signature that defines effector Treg cells. These signatures could not be extrapolated from transcriptome data. Unique cell-biological and metabolic features in Treg cells were defined, as well as specific adaptations in cytokine, TCR, and costimulatory receptor signaling pathways. One such adaptation—selective STAT4 deficiency—prevented destabilization of Treg cell identity and function by inflammatory cytokines, while these signals could still induce critical transcription factors and homing receptors via other pathways. Furthermore, our study revealed surface markers that identify FOXP3+CD4+ T cells with distinct functional properties. Our findings suggest that adaptation in signaling pathways protect Treg cell identity and present a resource for further research into Treg cell biology. Using high-resolution mass spectrometry and transcriptomics, Cuadrado et al. provide a molecular characterization of regulatory and conventional CD4+ T cell subsets, yielding markers to distinguish cells with different properties and insights into mechanisms that prevent regulatory T cells from exhibiting undesirable functional activities of the related but functionally antithetical conventional T cells.

SummarySteady-state dendritic cells (DCs) maintain peripheral T cell tolerance, whereas mature DCs generate immunity. CD70 is a costimulatory ligand acquired upon DC maturation. To determine its impact on T cell fate, we have generated mice that constitutively express CD70 in conventional DCs (cDCs). In these mice, naive CD4+ and CD8+ T cells spontaneously convert into effector cells. Administration of peptide without adjuvant, which is ordinarily tolerogenic, elicited tumor-eradicating CD8+ T cell responses and robust CD4+ T cell-independent memory. CD70 was also constitutively expressed in cDCs that inducibly present viral epitopes. In this case, tolerance induction was prevented as well. The antigen-presenting DCs generated protective immunity to virus infection and broke a pre-existing state of CD8+ T cell tolerance. Thus, the sole expression of CD70 by otherwise immature cDCs sufficed to convert CD8+ T cell tolerance into immunity, defining the importance of CD27-CD70 interactions at the interface between T cell and DC.

Summary CD4 + T cells optimize the cytotoxic T cell (CTL) response in magnitude and quality, by unknown molecular mechanisms. We here present the transcriptomic changes in CTLs resulting from CD4 + T cell help after anti-cancer vaccination or virus infection. The gene expression signatures revealed that CD4 + T cell help during priming optimized CTLs in expression of cytotoxic effector molecules and many other functions that ensured efficacy of CTLs throughout their life cycle. Key features included downregulation of PD-1 and other coinhibitory receptors that impede CTL activity, and increased motility and migration capacities. "Helped" CTLs acquired chemokine receptors that helped them reach their tumor target tissue and metalloprotease activity that enabled them to invade into tumor tissue. A very large part of the "help" program was instilled in CD8 + T cells via CD27 costimulation. The help program thus enhances specific CTL effector functions in response to vaccination or a virus infection.

SummaryT 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.

The interaction between the TNF receptor family member CD27 and its ligand CD70 provides a costimulatory signal for T cell expansion. Normally, tightly regulated expression of CD70 ensures the transient availability of this costimulatory signal. Mice expressing constitutive CD70 on B cells had higher peripheral T cell numbers that showed increased differentiation toward effector-type T cells. B cell numbers in CD70 transgenic (TG) mice progressively decreased in primary and secondary lymphoid organs. This B cell depletion was caused by CD27-induced production of IFNγ in T cells. We conclude that apart from its role in controlling the size of the activated T cell pool, CD27 ligation contributes to immunity by facilitating effector T cell differentiation.