Pathogenic CD8 T Cells in Multiple Sclerosis and Its Experimental Models

A growing body of evidence suggests that autoreactive CD8 T cells contribute to the disease process in multiple sclerosis (MS). Lymphocytes in MS plaques are biased toward the CD8 lineage, and MS patients harbor CD8 T cells specific for multiple central nervous system (CNS) antigens. Currently, there are relatively few experimental model systems available to study these pathogenic CD8 T cells in vivo. However, the few studies that have been done characterizing the mechanisms used by CD8 T cells to induce CNS autoimmunity indicate that several of the paradigms of how CD4 T cells mediate CNS autoimmunity do not hold true for CD8 T cells or for patients with MS. Thus, myelin-specific CD4 T cells are likely to be one of several important mechanisms that drive CNS disease in MS patients. The focus of this review is to highlight the current models of pathogenic CNS-reactive CD8 T cells and the molecular mechanisms these lymphocytes use when causing CNS inflammation and damage. Understanding how CNS-reactive CD8 T cells escape tolerance induction and induce CNS autoimmunity is critical to our ability to propose and test new therapies for MS

Neonatal-derived IL-17 producing dermal gammadelta T cells are required to prevent spontaneous atopic dermatitis

Atopic Dermatitis (AD) is a T cell-mediated chronic skin disease and is associated with altered skin barrier integrity. Infants with mutations in genes involved in tissue barrier fitness are predisposed towards inflammatory diseases, but most do not develop or sustain the diseases, suggesting that there exist regulatory immune mechanisms to prevent aberrant inflammation. The absence of one single murine dermal cell type, the innate neonatal-derived IL-17 producing gammadelta T (Tgammadelta17) cells, from birth resulted in spontaneous, highly penetrant AD with many of the major hallmarks of human AD. In Tgammadelta17 cell-deficient mice, basal keratinocyte transcriptome was altered months in advance of AD induction. Tgammadelta17 cells respond to skin commensal bacteria and the fulminant disease in their absence was driven by skin commensal bacteria dysbiosis. AD in this model was characterized by highly expanded dermal alphabeta T clonotypes that produce the type three cytokines, IL-17 and IL-22. These results demonstrate that neonatal Tgammadelta17 cells are innate skin regulatory T cells that are critical for skin homeostasis, and that IL-17 has dual homeostatic and inflammatory function in the skin

Generation of \u3b2 cell-specific human cytotoxic T cells by lentiviral transduction and their survival in immunodeficient human leucocyte antigen-transgenic mice

Several \u3b2 cell antigens recognized by T cells in the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D) are also T cell targets in the human disease. While numerous antigen-specific therapies prevent diabetes in NOD mice, successful translation of rodent findings to patients has been difficult. A human leucocyte antigen (HLA)-transgenic mouse model incorporating human \u3b2 cell-specific T cells might provide a better platform for evaluating antigen-specific therapies. The ability to study such T cells is limited by their low frequency in peripheral blood and the difficulty in obtaining islet-infiltrating T cells from patients. We have worked to overcome this limitation by using lentiviral transduction to 'reprogram' primary human CD8 T cells to express three T cell receptors (TCRs) specific for a peptide derived from the \u3b2 cell antigen islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP265-273 ) and recognized in the context of the human class I major histocompatibility complex (MHC) molecule HLA-A2. The TCRs bound peptide/MHC multimers with a range of avidities, but all bound with at least 10-fold lower avidity than the anti-viral TCR used for comparison. One exhibited antigenic recognition promiscuity. The \u3b2 cell-specific human CD8 T cells generated by lentiviral transduction with one of the TCRs released interferon (IFN)-\u3b3 in response to antigen and exhibited cytotoxic activity against peptide-pulsed target cells. The cells engrafted in HLA-A2-transgenic NOD-scid IL2r\u3b3(null) mice and could be detected in the blood, spleen and pancreas up to 5\u2009weeks post-transfer, suggesting the utility of this approach for the evaluation of T cell-modulatory therapies for T1D and other T cell-mediated autoimmune diseases

Register shifting of an insulin peptide–MHC complex allows diabetogenic T cells to escape thymic deletion

A single amino acid shift in TCR recognition of self peptide–MHC determines whether potentially diabetogenic CD4 T cells will be purged in the thymus or have the opportunity to undergo activation in the islets of Langerhans of mice

Banting Lecture 2009: An Unfinished Journey: Molecular Pathogenesis to Prevention of Type 1A Diabetes

The Banting Medal for Scientific Achievement Award is the American Diabetes Association's highest scientific award and honors an individual who has made significant, long-term contributions to the understanding of diabetes, its treatment, and/or prevention. The award is named after Nobel Prize winner Sir Frederick Banting, who codiscovered insulin treatment for diabetes

Prevention of type 1 diabetes in mice by tolerogenic vaccination with a strong agonist insulin mimetope

Subimmunogenic vaccination with an agonist mimetope of insulin converts naive T cells into regulatory T cells and prevents type 1 diabetes in NOD mice

Hydrophobic CDR3 residues promote the development of self-reactive T cells

Studies of individual T cell antigen receptors (TCRs) have shed some light on structural features that underlie self-reactivity. However, the general rules that can be used to predict whether TCRs are self-reactive have not been fully elucidated. Here we found that the interfacial hydrophobicity of amino acids at positions 6 and 7 of the complementarity-determining region CDR3β robustly promoted the development of self-reactive TCRs. This property was found irrespective of the member of the β-chain variable region (V[subscript β]) family present in the TCR or the length of the CDR3β. An index based on these findings distinguished V[subscript β]2[superscript +], V[subscript β]6[superscript +] and V[subscript β]8.2[superscript +] regulatory T cells from conventional T cells and also distinguished CD4[superscript +] T cells selected by the major histocompatibility complex (MHC) class II molecule I-A[superscript g7] (associated with the development of type 1 diabetes in NOD mice) from those selected by a non–autoimmunity-promoting MHC class II molecule I-Ab. Our results provide a means for distinguishing normal T cell repertoires versus autoimmunity-prone T cell repertoires

Modification of the carboxy-terminal flanking region of a universal influenza epitope alters CD4+ T-cell repertoire selection

Human CD4+ αβ T cells are activated via T-cell receptor recognition of peptide epitopes presented by major histocompatibility complex (MHC) class II (MHC-II). The open ends of the MHC-II binding groove allow peptide epitopes to extend beyond a central nonamer core region at both the amino- and carboxy-terminus. We have previously found that these non-bound C-terminal residues can alter T cell activation in an MHC allele-transcending fashion, although the mechanism for this effect remained unclear. Here we show that modification of the C-terminal peptide-flanking region of an influenza hemagglutinin (HA305−320) epitope can alter T-cell receptor binding affinity, T-cell activation and repertoire selection of influenza-specific CD4+ T cells expanded from peripheral blood. These data provide the first demonstration that changes in the C-terminus of the peptide-flanking region can substantially alter T-cell receptor binding affinity, and indicate a mechanism through which peptide flanking residues could influence repertoire selection

Autoimmune responses in T1DM : quantitative methods to understand onset, progression, and prevention of disease

Understanding the physiological processes that underlie autoimmune disorders and identifying biomarkers to predict their onset are two pressing issues that need to be thoroughly sorted out by careful thought when analyzing these diseases. Type 1 diabetes ( T1D ) is a typical example of such diseases. It is mediated by autoreactive cytotoxic CD4 + and CD8 + T‐cells that infiltrate the pancreatic islets of Langerhans and destroy insulin‐secreting β‐cells, leading to abnormal levels of glucose in affected individuals. The disease is also associated with a series of islet‐specific autoantibodies that appear in high‐risk subjects ( HRS ) several years prior to the onset of diabetes‐related symptoms. It has been suggested that T1D is relapsing‐remitting in nature and that islet‐specific autoantibodies released by lymphocytic B‐cells are detectable at different stages of the disease, depending on their binding affinity (the higher, the earlier they appear). The multifaceted nature of this disease and its intrinsic complexity make this disease very difficult to analyze experimentally as a whole. The use of quantitative methods, in the form of mathematical models and computational tools, to examine the disease has been a very powerful tool in providing predictions and insights about the underlying mechanism(s) regulating its onset and development. Furthermore, the models developed may have prognostic implications by aiding in the enrollment of HRS into trials for T1D prevention. In this review, we summarize recent advances made in determining T‐ and B‐cell involvement in T1D using these quantitative approaches and delineate areas where mathematical modeling can make further contributions in unraveling certain aspect of this disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106988/1/pedi12148.pd