Reverse plasticity: TGF-ß and IL-6 induce Th1-to-Th17-cell transdifferentiation in the gut.

Th17 cells are a heterogeneous population of pro-inflammatory T cells that have been shown to mediate immune responses against intestinal bacteria. Th17 cells are highly plastic and can transdifferentiate to Th1/17 cells or unconventional Th1 cells, which are highly pathogenic in animal models of immune-mediated diseases such as inflammatory bowel diseases. A recent European Journal of Immunology article by Liu et al. (Eur. J. Immunol. 2015. 45:1010-1018) showed, surprisingly, that Th1 cells have a similar plasticity, and could transdifferentiate to Th17 cells. Thus, IFN-γ-producing Th1 effector cells specific for an intestinal microbial antigen were shown to acquire IL-17-producing capacities in the gut in a mouse model of colitis, and in response to TGF-ß and IL-6 in vitro. TGF-ß induced Runx1, and together with IL-6 was shown to render the ROR-γt and IL-17 promoters in Th1 cells accessible for Runx1 binding. In this commentary, we discuss how this unexpected plasticity of Th1 cells challenges our view on the generation of Th1/17 cells with the capacity to co-produce IL-17 and IFN-γ, and consider possible implications of this Th1-to-Th17-cell conversion for therapies of inflammatory bowel diseases and protective immune responses against intracellular pathogens.

Osseous Consolidation of an Aseptic Delayed Union of a Lower Leg Fracture after Parathyroid Hormone Therapy - A Case Report.

The absence of osseous consolidation of a fracture within the normal time period is defined as delayed union or non-union. Both for the patient and from a socio-economic point of view, impaired fracture healing represents a major problem. Risk factors for a delayed fracture healing are insufficient immobilisation, poor adaptation of the fracture surfaces, interposition of soft tissue in the fracture gap, as well as circulation disturbances, metabolic disease, smoking and infections. In animal studies, a positive effect of parathyroid hormone (PTH) on fracture healing has been shown. PTH has a direct stimulatory effect on osteoblasts and osteoclasts. In addition, it appears to influence the effect of osseous growth factors. Few cases with the empiric off-label use of PTH that showed a tendency to support delayed or non-union fractures have been published. We report about a patient with a fracture of the lower leg and no osseous consolidation after 7 months. Four Months after therapy with 20 µg teriparatide per day for 8 weeks the fracture was consolidated and the patient had regained full and pain free weight bearing capacity of the leg with no reported side effects.

Bilateral Painful Ophthalmoplegia: A Case of Assumed Tolosa-Hunt Syndrome.

We present the case of a man of 47 years with vertical and horizontal paresis of view combined with periorbital pain that developed initially on the right side but extended after 3-4 days to the left. Gadolinum uptaking tissue in the cavernous sinus was shown by MRI of the orbital region in the T1 spin echo sequence with fat saturation (SEfs) with a slice thickness of 2 mm. As no other abnormalities were found and the pain resolved within 72 hours of treatment with cortison a bilateral Tolosa-Hunt Syndrome (THS) was assumed. THS is an uncommon cause for Painful Ophthalmoglegia (PO) and only few cases of bilateral appearance have been reported. Even though the diagnostic criteria for THS oblige unilateral symptoms we suggest that in patients with bilateral PO THS should not be excluded as a differential diagnosis. Further more when using MRI to detect granulomatous tissue in the orbital region the chosen sequence should be T1 SEfs and slice thickness should possibly be as low as 2 mm, as granulomas are often no larger than 1-2 mm.

Signal Strength and Metabolic Requirements Control Cytokine-Induced Th17 Differentiation of Uncommitted Human T Cells.

IL-17 production defines Th17 cells, which orchestrate immune responses and autoimmune diseases. Human Th17 cells can be efficiently generated with appropriate cytokines from precommitted precursors, but the requirements of uncommitted T cells are still ill defined. In standard human Th17 cultures, IL-17 production was restricted to CCR6(+)CD45RA(+) T cells, which expressed CD95 and produced IL-17 ex vivo, identifying them as Th17 memory stem cells. Uncommitted naive CD4(+) T cells upregulated CCR6, RORC2, and IL-23R expression with Th17-promoting cytokines but in addition required sustained TCR stimulation, late mammalian target of rapamycin (mTOR) activity, and HIF-1α to produce IL-17. However, in standard high-density cultures, nutrients like glucose and amino acids became progressively limiting, and mTOR activity was consequently not sustained, despite ongoing TCR stimulation and T cell proliferation. Sustained, nutrient-dependent mTOR activity also induced spontaneous IL-22 and IFN-γ production, but these cytokines had also unique metabolic requirements. Thus, glucose promoted IL-12-independent Th1 differentiation, whereas aromatic amino acid-derived AHR ligands were selectively required for IL-22 production. The identification of Th17 memory stem cells and the stimulation requirements for induced human Th17/22 differentiation have important implications for T cell biology and for therapies targeting the mTOR pathway.

IL-21 is a central memory T cell-associated cytokine that inhibits the generation of pathogenic Th1/17 effector cells.

IL-21 promotes Th17 differentiation, and Th17 cells that upregulate T-bet, IFN-γ, and GM-CSF drive experimental autoimmune diseases in mice. Anti-IL-21 treatment of autoimmune patients is therefore a therapeutic option, but the role of IL-21 in human T cell differentiation is incompletely understood. IL-21 was produced at high levels by human CD4(+) central memory T cells, suggesting that it is associated with early T cell differentiation. Consistently, it was inhibited by forced expression of T-bet or RORC2, the lineage-defining transcription factors of Th1 and Th17 effector cells, respectively. Although IL-21 was efficiently induced by IL-12 in naive CD4(+) T cells, it inhibited the generation of Th1 effector cells in a negative feedback loop. IL-21 was also induced by IL-6 and promoted Th17 differentiation, but it was not absolutely required. Importantly, however, IL-21 promoted IL-10 secretion but inhibited IFN-γ and GM-CSF production in developing Th17 cells, and consequently prevented the generation of polyfunctional Th1/17 effector cells. Moreover, in Th17 memory cells, IL-21 selectively inhibited T-bet upregulation and GM-CSF production. In summary, IL-21 is a central memory T cell-associated cytokine that promotes Th17 differentiation and IL-10 production, but inhibits the generation of potentially pathogenic Th1/17 effector cells. These findings shed new light on the role of IL-21 in T cell differentiation, and have relevant implications for anti-IL-21 therapy of autoimmune diseases.

Plasticity of human CD4 T cell subsets.

Human beings are exposed to a variety of different pathogens, which induce tailored immune responses and consequently generate highly diverse populations of pathogen-specific T cells. CD4(+) T cells have a central role in adaptive immunity, since they provide essential help for both cytotoxic T cell- and antibody-mediated responses. In addition, CD4(+) regulatory T cells are required to maintain self-tolerance and to inhibit immune responses that could damage the host. Initially, two subsets of CD4(+) helper T cells were identified that secrete characteristic effector cytokines and mediate responses against different types of pathogens, i.e., IFN-γ secreting Th1 cells that fight intracellular pathogens, and IL-4 producing Th2 cells that target extracellular parasites. It is now well established that this dichotomy is insufficient to describe the complexity of CD4(+) T cell differentiation, and in particular the human CD4 compartment contains a myriad of T cell subsets with characteristic capacities to produce cytokines and to home to involved tissues. Moreover, it has become increasingly clear that these T cell subsets are not all terminally differentiated cells, but that the majority is plastic and that in particular central memory T cells can acquire different properties and functions in secondary immune responses. In addition, there is compelling evidence that helper T cells can acquire regulatory functions upon chronic stimulation in inflamed tissues. The plasticity of antigen-experienced human T cell subsets is highly relevant for translational medicine, since it opens new perspectives for immune-modulatory therapies for chronic infections, autoimmune diseases, and cancer.