42 research outputs found
Follicular helper T cell differentiation in autoimmune diabetes: Role of the CD28 pathway
No full textThe CD28/CTLA-4 axis provides a crucial checkpoint in the maintenance of peripheral tolerance and T cell activation. In this thesis, we have explored the relationship between CD28 costimulation, CD4 T cell differentiation and the autoimmune disease, type 1 diabetes (T1D). The effect of varying the strength of CD28 engagement has been tested using flow cytometry and we have used single cell RNA sequencing to phenotype wildtype, CD28 heterozygous or CD28 deficient T cells responding to immunisation in vivo. This revealed that the level of CD28 engagement could markedly influence qualitative aspects of the T cell response, including follicular helper T cell (Tfh) differentiation, while T cell activation and proliferation were relatively insensitive to CD28 signal strength. The effect of CD28 costimulation blockade on Tfh differentiation was investigated using abatacept, a soluble CTLA-4 molecule. We found that abatacept inhibited immunisation-induced Tfh differentiation but this effect was decreased the longer after immunisation CD28 costimulation blockade was initiated. In a mouse model of diabetes, Tfh specific for pancreatic islet antigen were decreased after treatment with abatacept, suggesting an ongoing requirement for costimulation in Tfh responses to autoantigen. Furthermore, abatacept treatment reduced circulating Tfhlike cells in individuals with new onset T1D. With the help of unbiased analysis methods, that bypassed the requirement for manual gating, we were able to confirm the abatacept-induced Tfh reduction and also identify further T cell populations that were sensitive to CD28 costimulation blockade. Remarkably, by using predictive modelling and data-driven analysis, patient baseline Tfh profiles could be identified that were linked to the clinical response following abatacept treatment, as assessed by C-peptide retention at the 2-year time point. The findings presented in this thesis provide further insights into how CD28 costimulation shapes T cell responses and will aid our understanding of how treatments targeting the CD28 pathway are modulating immune responses
The link between circulating follicular helper T cells and autoimmunity
Get PDFFollicular helper T (TFH) cells provide help to B cells, supporting the formation of germinal centres that allow affinity maturation of antibody responses. Although usually located in secondary lymphoid organs, T cells bearing features of TFH cells can also be identified in human blood, and their frequency and phenotype are often altered in people with autoimmune diseases. In this Perspective article, I discuss the increase in circulating TFH cells seen in autoimmune settings and explore potential explanations for this phenomenon. I consider the multistep regulation of TFH cell differentiation by the CTLA4 and IL-2 pathways as well as by regulatory T cells and highlight that these same pathways are crucial for regulating autoimmune diseases. The propensity of infection to serve as a cue for TFH cell differentiation and a potential trigger for autoimmune disease development is also discussed. Overall, I postulate that alterations in pathways that regulate autoimmunity are coupled to alterations in TFH cell homeostasis, suggesting that this population may serve as a core sentinel of dysregulated immunity
Regulatory T Cells in Autoimmune Diabetes: Mechanisms of Action and Translational Potential
Get PDFSince the discovery of specialized T cells with regulatory function, harnessing the power of
these cells to ameliorate autoimmunity has been a major goal. Here we collate the evidence
that regulatory T cells (Treg) can inhibit Type 1 Diabetes in animal models and humans. We
discuss the anatomical sites and molecular mechanisms of Treg suppressive function in the
Type 1 Diabetes setting, citing evidence that Treg can function in both the pancreatic lymph
nodes and within the pancreatic lesion. Involvement of the CTLA-4 pathway, as well as TGFβ and IL-2 deprivation will be considered. Finally we summarize current efforts to manipulate
Treg therapeutically in individuals with Type 1 Diabetes. The translation of this research area
from bench to bedside is still in its infancy, but the remarkable therapeutic potential of
successfully manipulating Treg populations is clear to see
Dimers Aren't Forever: CD80 Breaks up with PD-L1
Get PDFTargeting the CTLA-4 and PD-1 “checkpoints” is an effective treatment for a number of cancers. In this issue of Immunity, Hui et al. reveal that interaction between a CTLA-4 ligand, CD80, and its counterpart in the PD-1 pathway, PD-L1, affects both PD-1 and CTLA-4 function, raising new questions about the biological effects of using checkpoint inhibitors alone and in combination
Tipping the balance: inhibitory checkpoints in intestinal homeostasis
Get PDFThe small intestinal and colonic lamina propria are populated with forkhead box P3 (FOXP3)+CD4+ regulatory T cells (Tregs) and interleukin-10-producing T cells that orchestrate intestinal tolerance to harmless microbial and food antigens. Expression of co-inhibitory receptors such as CTLA-4 and PD-1 serve as checkpoints to these cells controlling their T-cell receptor (TCR)-mediated and CD28-mediated activation and modulating the phenotype of neighboring antigen presenting cells. Recent discoveries on the diversity of co-inhibitory receptors and their selective cellular expression has shed new light on their tissue-dependent function. In this review, we provide an overview of the co-inhibitory pathways and checkpoints of Treg and effector T cells and their mechanisms of action in intestinal homeostasis. Better understanding of these inhibitory checkpoints is desired as their blockade harbors clinical potential for the treatment of cancer and their stimulation may offer new opportunities to treat chronic intestinal inflammation such as inflammatory bowel disease
Targeting co-stimulatory molecules in autoimmune disease
Get PDFTherapeutic targeting of immune checkpoints has garnered significant attention in the area of cancer immunotherapy, in which efforts have focused in particular on cytotoxic T lymphocyte antigen 4 (CTLA4) and PD1, both of which are members of the CD28 family. In autoimmunity, these same pathways can be targeted to opposite effect: to curb the over-exuberant immune response. The CTLA4 checkpoint serves as an exemplar, whereby CTLA4 activity is blocked by antibodies in cancer immunotherapy and augmented by the provision of soluble CTLA4 in autoimmunity. Here, we review the targeting of co-stimulatory molecules in autoimmune diseases, focusing in particular on agents directed at members of the CD28 or tumour necrosis factor receptor families. We present the state of the art in co-stimulatory blockade approaches, including rational combinations of immune inhibitory agents, and discuss the future opportunities and challenges in this field
Tumor burden induces a self-amplifying loop of myelopoiesis that Is mediated by NFκB-kit ligand signaling
No full textCancer cells induce an inflammatory microenvironment which consists of inflammatory cells, cytokines and chemokines. In the meanwhile, malignant tumors are associated with hematological abnormalities that disrupt homeostasis of hematopoiesis. Therefore how tumor burden influence hematopoiesis through inflammatory cytokines is studied in this thesis. Firstly, IFNγ was found to play a major role in lineagelowSca-1+C-kit+ (LSK) cell expansion by activating the expression of Sca-1 in lineagelowSca-1-C-kit+ cells in vivo and in vitro. This process was dependent on IFNγR1 signaling and the STAT1 pathway. The IFNγ-induced LSK cells had a higher proliferation potential than control LSK cells. Moreover, the IFNγ-induced hematopoiesis was more biased toward the differentiation of myeloid lineages. Therefore, our findings demonstrated a novel role of IFNγ in activating hematopoietic progenitor cells and provide a new insight into the clinical application of interferon. Secondly, in tumor-bearing mice, with the decline of hematopoiesis in bone marrow, spleens are greatly enlarged and harbor a greatly expanded population of hematopoietic progenitor cells (HPCs). While such HPCs can differentiate into both myeloid and lymphoid lineages when transplanted into tumor-free hosts, they preferentially give rise to myeloid lineages including macrophages/monocytes in tumor-bearing hosts. We further showed that macrophages/monocytes, derivatives of HPCs, are essential for the expansion of HPCs in spleen. Thus, HPCs and myeloid cells form a positive feedback loop in sustaining splenic myelopoiesis during tumorigenesis. This self-amplifying loop of HPCs and myeloid cells depends on an NFkB-Kit signaling cascade. Tumor-stimulated inflammatory factors are essential for the increased production of Kit ligands by macrophages/monocytes that drives splenic myelopoiesis. Targeting this HPC-myeloid loop may have potential in impeding tumor progression in cancer therapy. In conclusion, we found that the inflammatory cytokine IFNγ was demonstrated to enhance the expansion of hematopoietic stem cells (LSK cells) in vitro and in vivo, which provides important insights into studying the interaction between inflammation and hematopoiesis. Moreover, via mouse tumor models, we revealed the cellular and molecular basis for tumor-induced hematopoiesis and how such abnormal hematopoiesis influenced tumor progression. The information is important to understand the relationship between cancer and hematopoiesis, lending novel hope for cancer therapy.Ph. D.Includes bibliographical referencesIncludes vitaby Xin Zha
