Anti-CD3 Control of T Cells and Milk for Immune Development

Mansion Becomes Maternity Home- Life at Brocket Hall, Welwyn, Hertfordshire, 1942 D9026
Breast milk sugars are crucial for regulating the intestinal immune responses in newborns.
This week on TIBDI! Gene expression signatures of anti-TNFα non-responders are investigated, breast milk oligosaccharides regulate developing immune responses, and an anti-CD3 antibody offers hope for T cell regulation in the gut.

Inflammatory Signatures of Anti-TNFα Non-Responders

Even though anti-TNFα therapy for Crohn’s disease (CD) patients is very effective, up to 40% of patients are or become non-responders. To find out if there were differences in gene expression between these groups of patients, Dr. Raquel Franco Leal of the Hospital Clinic in Barcelona Spain examined mRNA levels of inflammatory genes in these two populations. She found that treatment with anti-TNFα effectively regulated many cytokines and chemokine genes despite the clinical outcome. However, those that achieved a clinical remission also had a number of changes in many other genes including IL1B, S100A8 and CXCL1. In contrast, refractory patients continued to have deregulated genes associated with pathways inducing IL17A. Besides introducing new drugs targets, these results reemphasize the importance of IL-17 pathways in CD.

Developing Immune Systems Need Milk

The complex immunoregulatory mechanisms needed to protect and control the human gut are developed early after birth, and are catalyzed by the colonization of the intestinal tract with bacteria. Suspecting that breast milk may protect the early intestinal tract from unwanted inflammatory responses, Dr. Y. He and colleagues investigated human milk oligosaccharides from colostrum (cHMOSs). Using human fetal intestine explants, they were able to determine that cHMOSs significantly altered immune gene expression. Their model suggests that cHMOSs attenuate pathogen-associated receptor signaling, simultaneously lowering immune cell activation and enhancing pathways needed for clearance, regulation and tissue repair.

Anti-Inflammatory Anti-CD3

T cells likely play an important role in inflammatory bowel disease (IBD) by maintaining inflammatory responses. Finding a way to specifically reduce or deactivate these cells in IBD patients could be a possible therapy. Dr. Anna Vossenkämper, together her colleagues, experimented with this idea using a special anti-CD3 antibody called otelixizumab, which is known to induce tolerance. Using mucosal biopsies from IBD patients, she was able to determine that otelixizumab could decrease pro-inflammatory cytokine production and lower the activity of multiple immune pathways. The antibody’s effects were determined to be dependent on IL-10 expression.

References

 

New and Exciting Ways to Control Th17 Differentiation

The basic unit of chromatin organization is the nucleosome, which comprises 147 bp of DNA wrapped ar
Controlling DNA packing could be a future way to alter T cell differentiation for IBD.
This week on TIBDI we get an overload on new Th17 research including Th17 induction via segmented filamentous bacteria and dendritic cells, the role of methyltransferases during T cell differentiation, and, my own article describing how TLR6 stimulation in the gut leads to increased Th17.

Segmented Filamentous Bacteria, DCs and Th17

It is already well described that segmented filamentous bacteria (SFB) are associated with the induction of Th17 cells in the gut, and that Th17 is associated with inflammatory bowel disease (IBD). However, the mechanisms behind the induction were not entirely clear. Yoshiyuki Goto and Casandra Panea of Columbia University Medical Center worked together to answer these questions, and found that dendritic cells (DCs) were the missing link. They determined that DCs presented SFB via MHC class II molecules to T cells, and induced SFB-directed Th17 cells. These interactions were not limited to areas of lymphoid tissue, but also happened in the small intestinal lamina propria. Interestingly, RORγt+ innate lymphoid cells simultaneously played an inhibiting role also via MHC class II molecules.

TLR6 Involved with Intestinal Inflammation

Pattern recognition receptors, like those from the Toll-like Receptor (TLR) family, alert the immune system when pathogens enter areas of the body. While this system is essential for fighting infection, the same receptors also induce inflammation during IBD. To learn more about TLR6 in intestinal inflammation, Dr. M.E. Morgan of Utrecht University in the Netherlands and her colleagues looked at immune responses induced in the gut both in vitro and in vivo. They found that stimulation of TLR6 in the gastrointestinal-associated lymphoid tissue supported the induction of Th1 and Th17 cells, and oral feeding of TLR6 ligands induced Th17 cells. Mice deficient in TLR6 had lower numbers of Th1 and Th17 cells, and were also protected from experimental colitis suggesting that TLR6 could be an interesting candidate for future IBD therapeutics.

Chromatin Control of T Cell Differentiation

Histone methyltransferases modify histones (by adding methyl groups to lysine residues) to control DNA packing and gene accessibility. These kinds changes could impact IBD. Recent research has indicated that the methyltransferase G9A controls a repressive modification called H3K9me2 that influences T cell differentiation. Dr. Frann Antignano of the University of British Columbia in Canada now sheds more light on this process. She found that G9A dynamically inhibited the differentiation of regulatory T cells and Th17, and that loss of G9A specifically led to more activity of the Foxp3 and Rorγt genes, which are the master transcription factor of regulatory T cells and Th17 cells respectively. Specifically eliminating G9A from T cells transferred during the T cell transfer colitis model increased regulatory T differentiation and lowered disease. This could mean that targeting histone methyltransferases could be a potential IBD therapy.

References

B Cells and Lactate Slow Down the Immune Response

Sodium lactate
A simple injection of sodium lactate can influence inflammasome activation.
This week on TIBDI: IL-35-secreting B cells inhibit immune responses; lactate interferes with inflammasome activation; and mucus and microbiota link nature and nurture.

New Inhibitory B Cells

B cells, known more for their antibody producing potential, also have a regulatory function when they secrete the anti-inflammatory cytokine interleukin (IL)-10. In a recent publication of Nature, Ping Shen and Toralf Roch of the German Rheumatology Research Center (DRFZ) in Germany discovered that IL-35-secreting B cells also play a similar role. They found that triggering co-stimulatory receptors on B cells induced IL-35 production and that IL-35-deficient B cells both hindered the recovery from a model of autoimmune disease (multiple sclerosis) and increased the immune response to an intestinal pathogen (Salmonella). Given the widespread influence of IL-35 producing B cells during infection and inflammatory disease, it will be interesting to see if they also are important for inflammatory bowel disease (IBD).

Lactate Slows Down Inflammasomes

Previous literature has indicated that the NLRP3 inflammasome is associated with Crohn’s disease (CD), and may be needed to induce protective immune responses against invading bacteria. Inflammasomes in macrophages are activated, in part, by danger signals. While danger signals mainly induce pro-inflammatory cytokine production, they also stimulate metabolic pathways, and one product that is produced is lactate. According to results produced by Rafaz Hoque of Yale University, lactate can function as a negative regulator of inflammasome activation. The team at Yale found that stimulation of the lactate receptor GPR81 could modify Toll-like receptor 4 signaling and lower subsequent NLRP3 activation. In vivo, lactate was effective at reducing acute organ injury in models with potent inflammasome activation, such as hepatitis and pancreatitis. This could mean that lactate modulates NLRP3 responses in Crohn’s disease as well.

Nature, Nurture and Mucus Production

Intestinal mucus has the important function of preventing bacterial contact with the epithelial surface. In fact, TMF-/- mice lacking a specific Golgi-associated protein (TMF/ARA160), which produce thick mucus, are generally protected from experimental colitis. However, Shai Bel of the Bar Ilan University in Israel has found that the protection is not derived from mucus alone. The intestinal microbiota are also important. The team found that the microbiota of TMF-/- mice is different from that of wild-types, and has larger populations of bacteria from the Firmicutes phylum. Even more importantly, transfer of these populations to normal mice, by co-housing, also transferred the colitis protection. This underscores the potential role of microbiota manipulation in lowering IBD susceptibility despite genetic predisposition.

Q: What’s your opinion about microbiota manipulation for IBD prevention? Feel free to contribute your thoughts here or on the LinkedIn discussion group.

References

The Crohn’s Disease Gender Bias and Neutrophils Disrupt the Gut

Neutrophils
Neutrophils (with purple irregular nuclei) can shed proteins that disrupt the intestinal barrier.
This week on TIBDI! Neutrophils shed a protein that disrupts the intestinal barrier, hormones and T cells are behind Crohn’s disease gender skewing, and CD31 is the newest way to make dendritic cells anti-inflammatory.

Neutrophils Bust Up the Intestinal Barrier

During inflammatory bowel disease (IBD), neutrophils gather at sites of inflammation and often migrate through the intestinal epithelial barrier. A new model described by Dr. Dominique A. Weber and Dr. Ronen Sumagin now shows how dangerous this behavior is for intestinal wound healing. They found that neutrophils shed junctional adhesion molecule-like protein (JAML) during epithelial transmigration. JAML binds to a receptor found on epithelial cells called coxsackie-adenovirus receptor (CAR), and JAML and CAR interactions cause epithelial barriers to become leaky. While this leakiness may be needed for initial efficient immune cell infiltration, shed JAML prevents the barrier from regaining normal function and stops wound closure. Experiments showed that blocking JAML-CAR interactions could lead to accelerated wound repair. This discovery could help treat IBD-induced intestinal ulcerations.

Why Crohn’s Disease Prefers Women

There is a general acceptance that the prevalence of Crohn’s disease (CD) is higher in women than in men. W.A. Goodman and R.R. Garg of Case Western Reserve University School of Medicine suspected that this gender bias might be the same in spontaneous models of CD. This is, indeed, the situation. Female SAMP1/YitFc (SAMP) mice were more predisposed to spontaneous CD and had impaired regulatory T cells with low frequencies as compared to the male SAMP mice. An investigation of the T cells revealed that male SAMP T cells responded much differently than female SAMP T cells to estrogen signals. While the male T cells responded by increasing immunosuppressive functions and expanding regulatory T cells, the female cells were resistant to these signals. Finding ways to make female T cells sensitive to estrogen signals could decrease female susceptibility to CD.

More Ways to Induce Anti-inflammatory Dendritic Cells

CD31 is expressed on many types of immune cells and endothelial cells, and it is mainly seen as an adhesion and migration molecule. Recent evidence has shown that it also has inhibitory function on T cells, which means that it might have inhibitory functions in other cells. Marc Clement of the French National Institute of Health and Medical Research (INSERM) has now found that this is, indeed, the situation with dendritic cells (DCs). Signaling via CD31 prevented DC maturation, migration and reduced pro-inflammatory signaling cascades. CD31-stimulated DC also preferentially polarized T cells towards a regulatory phenotype, and transfer of these DCs to a rodent model of multiple sclerosis delayed disease development. These results suggest that CD31 may also be potentially interesting for IBD.

References

New Insights about NOD2 and Th17 Differentiation

microRNA Mir210
This little piece of RNA has the power to influence Th17 differentiation.
This week on TIBDI: NOD2 and IFNγ work together to recruit cells to the small intestine, and a microRNA offers an interesting way to control Th17 differentiation.

NOD2 Behind Intestinal T Cell Recruitment

One of the most important receptors involved with Crohn’s disease (CD) is NOD2, a pattern recognition receptor that recognizes bacterial cell walls. Dr. Xingxin Wu of the Yale University School of Medicine investigated its involvement in an acute intestinal disease model induced by systemic anti-CD3. His results provide unique insight into infiltration dynamics of the characteristic CD8+ T cells found in the small intestine of this model. He discovered that NOD2 stimulation was needed for optimal infiltration. Without these signals, chemokines, specifically CXCR3-ligands, were not secreted by macrophages, dendritic cells and stromal cells. This prevented CD8+ T cells from leaving the circulation and entering the intestinal lamina propria. Moreover, the loss of CD8+ T cells in the small intestine led to reduced IFNγ, which also plays a role in stimulating immune cell chemotaxis.

Unexpected MicroRNA Control of Th17

During low oxygen conditions, immune cells upregulate transcription factors that turn on genes that help them cope with the hypoxia. One of these transcription factors, HIF-1α, also contributes to the differentiation of Th17 cells, which are important in the pathogenesis of inflammatory bowel disease (IBD). In an extremely interesting Nature Immunology publication, Dr. Haopeng Wang of the University of California in San Francisco described how the microRNA Mir210 inhibited HIF-1α expression and Th17 differentiation. MicroRNAs are small RNAs that prevent gene expression. By controlling the abundance of Mir210, he was also able to influence the numbers of Th17 T cells differentiated in vitro. Using the T cell transfer model of colitis with genetically manipulated T cells, which lacked Mir210 expression, he found that Mir210-deficient T cells caused increased numbers of Th17 and worsened symptoms. The authors suggest that drugs that function similarly to Mir210 could be interesting therapeutics.

References

  • Wang, H., Flach, H., Onizawa, M., Wei, L., McManus, M. T., & Weiss, A. (2014). Negative regulation of Hif1a expression and T. Nature Immunology, 1–10. doi:10.1038/ni.2846
  • Wu, X., Lahiri, A., Haines, G. K., Flavell, R. A., & Abraham, C. (2014). NOD2 Regulates CXCR3-Dependent CD8+ T Cell Accumulation in Intestinal Tissues with Acute Injury. The Journal of Immunology. doi:10.4049/jimmunol.1302436