CD147 modulates the differentiation of T‐helper 17 cells in patients with rheumatoid arthritis

The role of CD147 in regulation of rheumatoid arthritis (RA) is not fully elucidated. The aim of this study was to investigate the effect of cell‐to‐cell contact of activated CD14⁺ monocytes with CD4⁺ T cells, and the modulatory role of CD147 on T‐helper 17 (Th17) cells differentiation in patients with RA. Twenty confirmed active RA patients and twenty normal controls were enrolled. CD4⁺ T cells and CD14⁺ monocytes were purified by magnetic beads cell sorting. Cells were cultured under different conditions in CD4⁺ T cells alone, direct cell‐to‐cell contact co‐culture of CD4⁺ and CD14⁺ cells, or indirect transwell co‐culture of CD4⁺/CD14⁺ cells in response to LPS and anti‐CD3 stimulation with or without anti‐CD147 antibody pretreatments. The proportion of IL‐17‐producing CD4⁺ T cells (defined as Th17 cells) was determined by flow cytometry. The levels of interleukin (IL)‐17, IL‐6, and IL‐1β in the supernatants of cultured cells were measured by ELISA. The optimal condition for in vitro induction of Th17 cells differentiation was co‐stimulation with 0.1 μg/mL of LPS and 100 ng/mL of anti‐CD3 for 3 days under direct cell‐to‐cell contact co‐culture of CD4⁺ and CD14⁺ cells. Anti‐CD147 antibody reduced the proportion of Th17 cells, and also inhibited the productions of IL‐17, IL‐6, and IL‐1β in PBMC culture from RA patients. The current results revealed that Th17 differentiation required cell‐to‐cell contact with activated monocytes. CD147 promoted the differentiation of Th17 cells by regulation of cytokine production, which provided the evidence for pathogenesis and potential therapeutic targets for RA.     

IL‐17‐producing CD4+ T cells contribute to the loss of B‐cell tolerance in experimental autoimmune myasthenia gravis

The role of Th17 cells in the pathogenesis of autoantibody‐mediated diseases is unclear. Here, we assessed the contribution of Th17 cells to the pathogenesis of experimental autoimmune myasthenia gravis (EAMG), which is induced by repetitive immunizations with Torpedo californica acetylcholine receptor (tAChR). We show that a significant fraction of tAChR‐specific CD4⁺ T cells is producing IL‐17. IL‐17^ko mice developed fewer or no EAMG symptoms, although the frequencies of tAChR‐specific CD4⁺ T cells secreting IL‐2, IFN‐γ, or IL‐21, and the percentage of FoxP3⁺ T_reg cells were similar to WT mice. Even though the total anti‐tAChR antibody levels were equal, the complement fixating IgG2b subtype was reduced in IL‐17^ko as compared to WT mice. Most importantly, pathogenic anti‐murine AChR antibodies were significantly lower in IL‐17^ko mice. Furthermore, we confirmed the role of Th17 cells in EAMG pathogenesis by the reconstitution of TCR β/δ^ko mice with WT or IL‐17^ko CD4⁺ T cells. In conclusion, we show that the level of IgG2b and the loss of B‐cell tolerance, which results in pathogenic anti‐murine AChR‐specific antibodies, are dependent on IL‐17 production by CD4⁺ T cells. Thus, we describe here for the first time how Th17 cells are involved in the induction of classical antibody‐mediated autoimmunity.     

Flk‐1+ mesenchymal stem cells aggravate collagen‐induced arthritis by up‐regulating interleukin‐6

The immunomodulatory ability of mesenchymal stem cells (MSCs) may be used to develop therapies for autoimmune diseases. Flk‐1⁺ MSCs are a population of MSCs with defined phenotype and their safety has been evaluated in Phase 1 clinical trials. We designed this study to evaluate whether Flk‐1⁺ MSCs conferred a therapeutic effect on collagen‐induced arthritis (CIA), an animal model of rheumatic arthritis, and to explore the underlying mechanisms. Flk‐1⁺ MSCs, 1–2 × 10⁶, were injected into CIA mice on either day 0 or day 21. The clinical course of arthritis was monitored. Serum cytokine profile was determined by cytometric bead array kit or enzyme‐linked immunosorbent assay. Flk‐1⁺ MSCs and splenocytes co‐culture was conducted to explore the underlying mechanisms. Flk‐1⁺ MSCs did not confer therapeutic benefits. Clinical symptom scores and histological evaluation suggested aggravation of arthritis in mice treated with MSCs at day 21. Serum cytokine profile analysis showed marked interleukin (IL)‐6 secretion immediately after MSC administration. Results of in vitro culture of splenocytes confirmed that the addition of Flk‐1⁺ MSCs promoted splenocyte proliferation and increased IL‐6 and IL‐17 secretion. Moreover, splenocyte proliferation was also enhanced in mice treated with MSCs at day 21. Accordingly, MSCs at low concentrations were found to promote lipopolysaccharide‐primed splenocytes proliferation in an in vitro co‐culture system. We propose that Flk‐1⁺ MSCs aggravate arthritis in CIA model by at least up‐regulating secretion of IL‐6, which favours Th17 differentiation. When Flk‐1⁺ MSCs are used for patients, we should be cautious about subjects with rheumatoid arthritis.     

Blocking of LFA‐1 enhances expansion of Th17 cells induced by human CD14+CD16++ nonclassical monocytes

Among human peripheral blood (PB) monocyte (Mo) subsets, the classical CD14⁺⁺CD16^? (cMo) and intermediate CD14⁺⁺CD16⁺ (iMo) Mos are known to activate pathogenic Th17 responses, whereas the impact of nonclassical CD14⁺CD16⁺⁺ Mo (nMo) on T‐cell activation has been largely neglected. The aim of this study was to obtain new mechanistic insights on the capacity of Mo subsets from healthy donors (HDs) to activate IL‐17⁺ T‐cell responses in vitro, and assess whether this function was maintained or lost in states of chronic inflammation. When cocultured with autologous CD4⁺ T cells in the absence of TLR‐2/NOD2 agonists, PB nMos from HDs were more efficient stimulators of IL‐17‐producing T cells, as compared to cMo. These results could not be explained by differences in Mo lifespan and cytokine profiles. Notably, however, the blocking of LFA‐1/ICAM‐1 interaction resulted in a significant increase in the percentage of IL‐17⁺ T cells expanded in nMo/T‐cell cocultures. As compared to HD, PB Mo subsets of patients with rheumatoid arthritis were hampered in their T‐cell stimulatory capacity. Our new insights highlight the role of Mo subsets in modulating inflammatory T‐cell responses and suggest that nMo could become a critical therapeutic target against IL‐17‐mediated inflammatory diseases.     

CD11b regulates the Treg/Th17 balance in murine arthritis via IL‐6

Th17 cells are often associated with autoimmunity and been shown to be increased in CD11b^?/? mice. Here, we examined the role of CD11b in murine collagen‐induced arthritis (CIA). C57BL/6 and CD11b^?/? resistant mice were immunized with type II collagen. CD11b^?/? mice developed arthritis with early onset, high incidence, and sustained severity compared with C57BL/6 mice. We observed a marked leukocyte infiltration, and histological examinations of the arthritic paws from CD11b^?/? mice revealed that the cartilage was destroyed in association with strong lymphocytic infiltration. The CD11b deficiency led to enhanced Th17‐cell differentiation. CD11b^?/? dendritic cells (DCs) induced much stronger IL‐6 production and hence Th17‐cell differentiation than wild‐type DCs. Treatment of CD11b^?/? mice after establishment of the Treg/Th17 balance with an anti‐IL‐6 receptor mAb significantly suppressed the induction of Th17 cells and reduced arthritis severity. Finally, the severe phenotype of arthritis in CD11b^?/? mice was rescued by adoptive transfer of CD11b⁺ DCs. Taken together, our results indicate that the resistance to CIA in C57BL/6 mice is regulated by CD11b via suppression of IL‐6 production leading to reduced Th17‐cell differentiation. Therefore, CD11b may represent a susceptibility factor for autoimmunity and could be a target for future therapy.     

Novel therapeutic compound tuftsin–phosphorylcholine attenuates collagen‐induced arthritis

Treatment with helminthes and helminthes ova improved the clinical symptoms of several autoimmune diseases in patients and in animal models. Phosphorylcholine (PC) proved to be the immunomodulatory molecule. We aimed to decipher the tolerogenic potential of tuftsin–PC (TPC), a novel helminth‐based compound in collagen‐induced arthritis (CIA) a mouse model of rheumatoid arthritis (RA). CIA DBA/1 mice were treated with TPC subcutaneously (5 µg/0.1 ml) or orally (250 µg/0.1 ml), starting prior to disease induction. The control groups were treated with PBS. Collagen antibodies were tested by enzyme‐linked immunosorbent assay (ELISA), cytokine protein levels by ELISA kits and regulatory T (T_reg) and regulatory B (B_reg) cell phenotypes by fluorescence‐activated cell sorter (FACS). TPC‐treated mice had a significantly lower arthritis score of 1.5 in comparison with control mice 11.8 (P < 0.0001) in both subcutaneous and orally treated groups at day 31. Moreover, histology analysis demonstrated highly inflamed joints in control mice, whereas TPC‐treated mice maintained normal joint structure. Furthermore, TPC decreased the titres of circulating collagen II antibodies in mice sera (P < 0.0001), enhanced expression of IL‐10 (P < 0.0001) and inhibited production of tumour necrosis factor (TNF)‐α, interleukin (IL)?17 and IL‐1β (P < 0.0001). TPC significantly expanded the CD4⁺CD25⁺ forkhead box protein 3 (FoxP3⁺) T_reg cells and CD19⁺IL‐10⁺CD5^highCD1d^highT cell immunoglobulin mucin‐1 (TIM‐1⁺) B_reg cell phenotypes (P < 0.0001) in treated mice. Our data indicate that treatment with TPC attenuates CIA in mice demonstrated by low arthritic score and normal joints histology. TPC treatment reduced proinflammatory cytokines and increased anti‐inflammatory cytokine expression, as well as expansion of T_reg and B_reg cells. Our results may lead to a new approach for a natural therapy for early rheumatoid arthritis onset.     

In vitro‐induced Th17 cells fail to induce inflammation in vivo and show an impaired migration into inflamed sites

Recently, IL‐17 produced by Th17 cells was described as pro‐inflammatory cytokine with an eminent role in autoimmune diseases, e.g. rheumatoid arthritis. A lack of IL‐17 leads to amelioration of collagen‐induced arthritis. IL‐17 induction in naïve CD4⁺ T cells depends on IL‐6 and TGF‐β and is enhanced by IL‐23. The in vivo inflammatory potential of in vitro‐primed Th17 cells however, remains unclear. Here, we show that, although IL‐17 neutralisation results in amelioration of murine OVA‐induced arthritis, in vitro‐primed Th17 cells cannot exacerbate arthritic symptoms after adoptive transfer. Furthermore, Th17 cells cannot induce an inflammatory delayed type hypersensitivity reaction because they fail to migrate into inflamed sites, possibly due to the lack of CXCR3 expression. Also, re‐isolated Th17 cells acquired IFN‐γ expression, indicating instability of the Th17 phenotype. Taken together, the data show that IL‐6, TGF‐β and IL‐23 might not provide sufficient signals to induce “fully qualified” Th17 cells.     

Protection against collagen‐induced arthritis in mice afforded by the parasitic worm product,ES‐62, is associated with restoration of the levels of interleukin‐10‐producing B cells and reduced plasma cell infiltration of the joints

We have previously reported that ES‐62, a molecule secreted by the parasitic filarial nematode Acanthocheilonema viteae, protects mice from developing collagen‐induced arthritis (CIA). Together with increasing evidence that worm infection may protect against autoimmune conditions, this raises the possibility that ES‐62 may have therapeutic potential in rheumatoid arthritis and hence, it is important to fully understand its mechanism of action. To this end, we have established to date that ES‐62 protection in CIA is associated with suppressed T helper type 1 (Th1)/Th17 responses, reduced collagen‐specific IgG2a antibodies and increased interleukin‐10 (IL‐10) production by splenocytes. IL‐10‐producing regulatory B cells have been proposed to suppress pathogenic Th1/Th17 responses in CIA: interestingly therefore, although the levels of IL‐10‐producing B cells were decreased in the spleens of mice with CIA, ES‐62 was found to restore these to the levels found in naive mice. In addition, exposure to ES‐62 decreased effector B‐cell, particularly plasma cell, infiltration of the joints, and such infiltrating B cells showed dramatically reduced levels of Toll‐like receptor 4 and the activation markers, CD80 and CD86. Collectively, this induction of hyporesponsiveness of effector B‐cell responses, in the context of the resetting of the levels of IL‐10‐producing B cells, is suggestive of a modulation of the balance between effector and regulatory B‐cell responses that may contribute to ES‐62‐mediated suppression of CIA‐associated inflammation and inhibition of production of pathogenic collagen‐specific IgG2a antibodies.     

DRB1*0402 may influence arthritis by promoting naive CD4+ T‐cell differentiation in to regulatory T cells

HLA‐DRB1*0401 expression in humans has been associated with a predisposition to developing rheumatoid arthritis (RA) and collagen‐induced arthritis (CIA), while HLA‐DRB1*0402 is not associated with susceptibility. Here, we determined if mice transgenic (Tg) for human *0401 have a CD4⁺ T‐cell repertoire that predetermines proinflammatory cytokine production. The data show that both *0401 and *0402 Tg mice can produce TH1/TH17 cytokines, although the kinetics of response may be different. However, in the context of antigen‐specific responses in a CIA model, *0402 Tg mice generate a TH2 response that may explain their resistance to developing arthritis. In addition, a significant subset of naïve CD4⁺ T cells from *0402 Tg mice can be activated in polarizing conditions to differentiate into Treg cells that produce IFN‐γ. *0401 Tg mice harbor memory CD4⁺ T cells that differentiate into IL‐17⁺ cells in various polarizing conditions. Our data suggest that *0401 Tg mice generate a strong immune response to lipopolysaccharide and may be efficient in clearing infection, and may *0401 have been evolutionarily selected for this ability. Autoimmunity, such as RA, could likely be a bystander effect of the cytokine storm that, along with the presence of low Treg‐cell numbers in *0401 Tg mice, causes immune dysregulation.     

Antigen‐specific over‐expression of human cartilage glycoprotein 39 on CD4+CD25+ forkhead box protein 3+ regulatory T cells in the generation of glucose‐6‐phosphate isomerase‐induced arthritis

Human cartilage gp‐39 (HC gp‐39) is a well‐known autoantigen in rheumatoid arthritis (RA). However, the exact localization, fluctuation and function of HC gp‐39 in RA are unknown. Therefore, using a glucose‐6‐phosphate isomerase (GPI)‐induced model of arthritis, we investigated these aspects of HC gp‐39 in arthritis. The rise in serum HC gp‐39 levels was detected on the early phase of GPI‐induced arthritis (day 7) and the HC gp‐39 mRNA was increased significantly on splenic CD4⁺T cells on day7, but not on CD11b⁺cells. Moreover, to identify the characterization of HC gp‐39⁺CD4⁺T cells, we assessed the analysis of T helper (Th) subsets. As a result, HC gp‐39 was expressed dominantly in CD4⁺CD25⁺ forkhead box protein 3 (FoxP3)⁺ refulatory T cells (T_reg), but not in Th1, Th2 or Th17 cells. Furthermore, to investigate the effect of HC gp‐39 to CD4⁺T cells, T cell proliferation assay and cytokine production from CD4⁺T cells using recombinant HC gp‐39 was assessed. We found that GPI‐specific T cell proliferation and interferon (IFN)‐γ or interleukin (IL)‐17 production were clearly suppressed by addition of recombinant HC gp‐39. Antigen‐specific over‐expression of HC gp‐39 in splenic CD4⁺CD25⁺ FoxP3⁺ T_reg cells occurs in the induction phase of GPI‐induced arthritis, and addition of recombinant HC gp‐39 suppresses antigen‐specific T‐cell proliferation and cytokine production, suggesting that HC gp‐39 in CD4⁺ T cells might play a regulatory role in arthritis.     

TGF‐β indirectly favors the development of human Th17 cells by inhibiting Th1 cells

Human Th17 clones and circulating Th17 cells showed lower susceptibility to the anti‐proliferative effect of TGF‐β than Th1 and Th2 clones or circulating Th1‐oriented T cells, respectively. Accordingly, human Th17 cells exhibited lower expression of clusterin, and higher Bcl‐2 expression and reduced apoptosis in the presence of TGF‐β, in comparison with Th1 cells. Umbilical cord blood naïve CD161⁺CD4⁺ T cells, which contain the precursors of human Th17 cells, differentiated into IL‐17A‐producing cells only in response to IL‐1β plus IL‐23, even in serum‐free cultures. TGF‐β had no effect on constitutive RORγt expression by umbilical cord blood CD161⁺ T cells but it increased the relative proportions of CD161⁺ T cells differentiating into Th17 cells in response to IL‐1β plus IL‐23, whereas under the same conditions it inhibited both T‐bet expression and Th1 development. These data suggest that TGF‐β is not critical for the differentiation of human Th17 cells, but indirectly favors their expansion because Th17 cells are poorly susceptible to its suppressive effects.     

Differential control of CD4+ T‐cell subsets by the PD‐1/PD‐L1 axis in a mouse model of allergic asthma

Studies examining the role of PD‐1 family members in allergic asthma have yielded conflicting results. Using a mouse model of allergic asthma, we demonstrate that blockade of PD‐1/PD‐L1 has distinct influences on different CD4⁺ T‐cell subsets. PD‐1/PD‐L1 blockade enhances airway hyperreactivity (AHR), not by altering the magnitude of the underlying Th2‐type immune response, but by allowing the development of a concomitant Th17‐type immune response. Supporting differential CD4⁺ T‐cell responsiveness to PD‐1‐mediated inhibition, naïve PD‐1^?/? mice displayed elevated Th1 and Th17 levels, but diminished Th2 cytokine levels, and ligation of PD‐1 in WT cells limited cytokine production by in vitro polarized Th1 and Th17 cells, but slightly enhanced cytokine production by in vitro polarized Th2 cells. Furthermore, PD‐1 ligation enhanced Th2 cytokine production by naïve T cells cultured under nonpolarizing conditions. These data demonstrate that different CD4⁺ T‐cell subsets respond differentially to PD‐1 ligation and may explain some of the variable results observed in control of allergic asthma by the PD‐1 family members. As the PD‐1/PD‐L1 axis limits asthma severity by constraining Th17 cell activity, this suggests that severe allergic asthma may be associated with a defective PD‐1/PD‐L1 regulatory axis in some individuals.     

IL‐12‐polarized Th1 cells produce GM‐CSF and induce EAE independent of IL‐23

CD4⁺ T‐helper (Th) cells reactive against myelin antigens mediate the mouse model experimental autoimmune encephalomyelitis (EAE) and have been implicated in the pathogenesis of multiple sclerosis (MS). It is currently debated whether encephalitogenic Th cells are heterogeneous or arise from a single lineage. In the current study, we challenge the dogma that stimulation with the monokine IL‐23 is universally required for the acquisition of pathogenic properties by myelin‐reactive T cells. We show that IL‐12‐modulated Th1 cells readily produce IFN‐γ and GM‐CSF in the CNS of mice and induce a severe form of EAE via an IL‐23‐independent pathway. Th1‐mediated EAE is characterized by monocyte‐rich CNS infiltrates, elicits a strong proinflammatory cytokine response in the CNS, and is partially CCR2 dependent. Conversely, IL‐23‐modulated, stable Th17 cells induce EAE with a relatively mild course via an IL‐12‐independent pathway. These data provide definitive evidence that autoimmune disease can be driven by distinct CD4⁺ T‐helper‐cell subsets and polarizing factors.     

Enhanced suppressor function of TIM‐3+FoxP3+ regulatory T cells

T‐cell immunoglobulin and mucin domain 3 (TIM‐3) is an Ig‐superfamily member expressed on IFN‐γ‐secreting Th1 and Tc1 cells and was identified as a negative regulator of immune tolerance. TIM‐3 is expressed by a subset of activated CD4⁺ T cells, and anti‐CD3/anti‐CD28 stimulation increases both the level of expression and the number of TIM‐3⁺ T cells. In mice, TIM‐3 is constitutively expressed on natural regulatory T (Treg) cells and has been identified as a regulatory molecule of alloimmunity through its ability to modulate CD4⁺ T‐cell differentiation. Here, we examined TIM‐3 expression on human Treg cells to determine its role in T‐cell suppression. In contrast to mice, TIM‐3 is not expressed on Treg cells ex vivo but is upregulated after activation. While TIM‐3⁺ Treg cells with increased gene expression of LAG3, CTLA4, and FOXP3 are highly efficient suppressors of effector T (Teff) cells, TIM‐3^? Treg cells poorly suppressed Th17 cells as compared with their suppression of Th1 cells; this decreased suppression ability was associated with decreased STAT‐3 expression and phosphorylation and reduced gene expression of IL10, EBI3, GZMB, PRF1, IL1Rα, and CCR6. Thus, our results suggest that TIM‐3 expression on Treg cells identifies a population highly effective in inhibiting pathogenic Th1‐ and Th17‐cell responses.     

Activated γδ T cells inhibit osteoclast differentiation and resorptive activity in vitro

Extensive evidence suggests that the immune system exerts powerful effects on bone cells, particularly in chronic disease pathologies such as rheumatoid arthritis (RA). The chronic inflammatory state in RA, particularly the excessive production of T cell‐derived proinflammatory cytokines such as tumour necrosis factor (TNF)‐α and interleukin (IL)‐17, triggers bone erosions through the increased stimulation of osteoclast formation and activity. While evidence supports a role for IL‐17 and TNF‐α secreted by conventional CD4⁺ T cells in RA, recent evidence in animal models of RA have implicated γδ T cells as a major producer of pathogenic IL‐17. However, the capacity of γδ T cells to influence osteoclast formation and activity in humans has not yet been investigated widely. To address this issue we investigated the effects of γδ T cells on osteoclast differentiation and resorptive activity. We have demonstrated that anti‐CD3/CD28‐stimulated γδ T cells or CD4⁺ T cells inhibit human osteoclast formation and resorptive activity in vitro. Furthermore, we assessed cytokine production by CD3/CD28‐stimulated γδ T cells and observed a lack of IL‐17 production, with activated γδ T cells producing abundant interferon (IFN)‐γ. The neutralization of IFN‐γ markedly restored the formation of osteoclasts from precursor cells and the resorptive activity of mature osteoclasts, suggesting that IFN‐γ is the major factor responsible for the inhibitory role of activated γδ T cells on osteoclastogenesis and resorptive activity of mature osteoclasts. Our work therefore provides new insights on the interactions between γδ T cells and osteoclasts in humans.     

APRIL (TNFSF13) regulates collagen‐induced arthritis,IL‐17 production and Th2 response

A proliferation‐inducing ligand (APRIL or TNFSF13) shares receptors with B‐cell activation factor of the TNF family (BAFF) on B and T cells. Although much is known about the function of APRIL in B cells, its role in T cells remains unclear. Blocking both BAFF and APRIL suggested that BAFF and/or APRIL contributed to collagen‐induced arthritis (CIA); however, the role of APRIL alone in CIA remained unresolved. We show here that, in vitro, our newly generated APRIL^?/? mice exhibited increased T‐cell proliferation, enhanced Th2 cytokine production under non‐polarizing conditions, and augmented IL‐13 and IL‐17 production under Th2 polarizing conditions. Upon immunization with OVA and aluminum potassium sulfate, APRIL^?/? mice responded with an increased antigen‐specific IgG1 response. We also show that in APRIL^?/? mice, the incidence of CIA was significantly reduced compared with WT mice in parallel with diminished levels of antigen‐specific IgG2a autoantibody and IL‐17 production. Our data indicate that APRIL plays an important role in the regulation of cytokine production and that APRIL‐triggered signals contribute to arthritis. Blockade of APRIL thus may be a valuable adjunct in the treatment of rheumatoid arthritis.     

Functional characterization of myeloid‐derived suppressor cell subpopulations during the development of experimental arthritis

Recent evidence indicates the existence of subpopulations of myeloid‐derived suppressor cells (MDSCs) with distinct phenotypes and functions. Here, we characterized the role of MDSC subpopulations in the pathogenesis of autoimmune arthritis in a collagen‐induced arthritis (CIA) mouse model. The splenic CD11b⁺Gr‐1⁺ MDSC population expanded in CIA mice, and these cells could be subdivided into polymorphonuclear (PMN) and mononuclear (MO) MDSC subpopulations based on Ly6C and Ly6G expression. During CIA, the proportion of splenic MO‐MDSCs was increased in association with the severity of joint inflammation, while PMN‐MDSCs were decreased. MO‐MDSCs expressed higher levels of surface CD40 and CD86 protein, but lower levels of Il10, Tgfb1, Ccr5, and Cxcr2 mRNA. PMN‐MDSCs exhibited a more potent capacity to suppress polyclonal T‐cell proliferation in vitro, compared with MO‐MDSCs. Moreover, the adoptive transfer of PMN‐MDSCs, but not MO‐MDSCs, decreased joint inflammation, accompanied by reduced levels of serum cytokine secretion and the frequencies of Th1 and Th17 cells in draining lymph nodes. These results suggest that there could be a shift from potently suppressive PMN‐MDSCs to poorly suppressive MO‐MDSCs during the development of experimental arthritis, which might reflect the failure of expanded MDSCs to suppress autoimmune arthritis.     

Boswellic acids reduce Th17 differentiation via blockade of IL‐1β‐mediated IRAK1 signaling

Interferon‐gamma producing CD4⁺ T (Th1) cells and IL‐17‐producing CD4⁺ T (Th17) cells are involved in the pathogenesis of several autoimmune diseases including multiple sclerosis. Therefore, the development of treatment strategies controlling the generation and expansion of these effector cells is of high interest. Frankincense, the resin from trees of the genus Boswellia, and particularly its prominent bioactive compound acetyl‐11‐keto‐β‐boswellic acid (AKBA), have potent anti‐inflammatory properties. Here, we demonstrate that AKBA is able to reduce the differentiation of human CD4⁺ T cells to Th17 cells, while slightly increasing Th2‐ and Treg‐cell differentiation. Furthermore, AKBA reduces the IL‐1β‐triggered IL‐17A release of memory Th17 cells. AKBA may affect IL‐1β signaling by preventing IL‐1 receptor‐associated kinase 1 phosphorylation and subsequently decreasing STAT3 phosphorylation at Ser727, which is required for Th17‐cell differentiation. The effects of AKBA on Th17 differentiation and IL‐17A release make the compound a good candidate for potential treatment of Th17‐driven diseases.     

Pathogenic T helper type 17 cells contribute to type 1 diabetes independently of interleukin‐22

We have shown that pathogenic T helper type 17 (Th17) cells differentiated from naive CD4⁺ T cells of BDC2·5 T cell receptor transgenic non‐obese diabetic (NOD) mice by interleukin (IL)‐23 plus IL‐6 produce IL‐17, IL‐22 and induce type 1 diabetes (T1D). Neutralizing interferon (IFN)‐γ during the polarization process leads to a significant increase in IL‐22 production by these Th17 cells. We also isolated IL‐22‐producing Th17 cells from the pancreas of wild‐type diabetic NOD mice. IL‐27 also blocked IL‐22 production from diabetogenic Th17 cells. To determine the functional role of IL‐22 produced by pathogenic Th17 cells in T1D we neutralized IL‐22 in vivo by using anti‐IL‐22 monoclonal antibody. We found that blocking IL‐22 did not alter significantly adoptive transfer of disease by pathogenic Th17 cells. Therefore, IL‐22 is not required for T1D pathogenesis. The IL‐22Rα receptor for IL‐22 however, increased in the pancreas of NOD mice during disease progression and based upon our and other studies we suggest that IL‐22 may have a regenerative and protective role in the pancreatic islets.     

Alpha2beta1 integrin is the major collagen‐binding integrin expressed on human Th17 cells

Growing evidence indicates that collagen‐binding integrins are important costimulatory molecules of effector T cells. In this study, we demonstrate that the major collagen‐binding integrin expressed by human Th17 cells is alpha2beta1 (α2β1) or VLA‐2, also known as the receptor for collagen I on T cells. Our results show that human naïve CD4⁺ T cells cultured under Th17 polarization conditions preferentially upregulate α2β1 integrin rather than α1β1 integrin, which is the receptor for collagen IV on T cells. Double staining analysis for integrin receptors and intracellular IL‐17 showed that α2 integrin but not α1 integrin is associated with Th17 cells. Cell adhesion experiments demonstrated that Th17 cells attach to collagen I and collagen II using α2β1 integrin but did not attach to collagen IV. Functional studies revealed that collagens I and II but not collagen IV costimulate the production of IL‐17A, IL‐17F and IFN‐γ by human Th17 cells activated with anti‐CD3. These results identify α2β1 integrin as the major collagen receptor expressed on human Th17 cells and suggest that it can be an important costimulatory molecule of Th17 cell responses.