T Cell-Mediated Autoimmune Disease Due to Low-Affinity Crossreactivity to Common Microbial Peptides

Autoreactive CD8+ T lymphocytes play a key role in the pathogenesis of several autoimmune diseases. It is not yet well understood how autoreactive CD8+ T cells, which express TCRs with low reactivity toward self-Ags, gain the ability to respond to autoantigens to cause disease. Previously, we have shown that prior stimulation of CD8+ T cells with synergistic combinations of cytokines produced by the innate immune response, such as IL-21 and IL-15, induces Ag-independent proliferation. Such “cytokine-primed” CD8 T cells displayed increased responsiveness to limiting quantities of the cognate Ag. In this paper, we report that prior stimulation with IL-15 and IL-21 also enables CD8+ T cells to respond to weakly agonistic TCR ligands, resulting in proliferation, cytokine secretion, and cytolytic activity. Using a transgenic mouse model of autoimmune diabetes, we show that cytokine-primed autoreactive CD8+ T cells induce disease following stimulation by weak TCR ligands, but their diabetogenic potential is dependent on continuous availability of IL-15 in vivo. These findings suggest that inflammatory cytokines could facilitate the triggering of autoreactive CD8+ T cells by weak autoantigens, and this mechanism may have important implications for autoimmune diseases associated with microbial infections and chronic inflammation.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Exposure to IL-15 and IL-21 Enables Autoreactive CD8 T Cells To Respond to Weak Antigens and Cause Disease in a Mouse Model of Autoimmune Diabetes

Ramanathan

Dubois

Chen

et al. 2011

“…+ T cell-mediated demyelinating disease with pathological similarities to MS and is widely used as an animal model of MS (1,2). EAE is induced in susceptible mice by immunization with whole myelin proteins, MOG peptide, or PLP peptide emulsified in CFA, or by adoptive transfer of autoreactive T cells to normal recipient mice (3)(4)(5)(6).…”

Section: Ultiple Sclerosis (Ms) Is the Most Common Autoimmune Inflamentioning

confidence: 99%

Antiasthmatic Drugs Targeting the Cysteinyl Leukotriene Receptor 1 Alleviate Central Nervous System Inflammatory Cell Infiltration and Pathogenesis of Experimental Autoimmune Encephalomyelitis

Wang

et al. 2011

Cysteinyl leukotrienes (CysLTs) are potent proinflammatory mediators and are considered to play a key role in inflammatory diseases such as asthma. Antagonists targeting the receptor of CysLTs (CysLT1) are currently used as antiasthmatic drugs. CysLTs have also been implicated in other inflammatory reactions. In this study, we report that in experimental autoimmune encephalomyelitis animals, CysLT1 is upregulated in immune tissue and the spinal cord, and CysLT levels in the blood and cerebrospinal fluid are also higher than in normal mice. Two clinically used antiasthma drugs, montelukast and zafirlukast, both targeting CysLT1, effectively block the CNS infiltration of inflammatory cells and thus reduce the incidence, peak severity, and cumulative clinical scores. Further study indicated that CysLT1 signaling does not affect the differentiation of pathogenic T helper cells. It might affect the pathogenesis of experimental autoimmune encephalomyelitis by increasing the secretion of IL-17 from myelin oligodendrocyte glycoprotein-specific T cells, increasing the permeability of the blood–brain barrier and inducing chemotaxis of T cells. These effects can be blocked by CysLT1 antagonists. Our findings indicate that the antiasthmatic drugs against CysLT1 can also be used to treat multiple sclerosis.

“…One of the facets of polyspecificity in the context of autoimmune diseases is molecular mimicry, defined as sequence similarities between foreign and self-antigens that result in the cross-activation of autoreactive T and B cells by microbial Ags (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). Originally, an important degree of sequence homology was considered necessary to explain molecular mimicry, but subsequent extensive dissection with synthetic peptide combinatorial libraries revealed that TCR Ag recognition is quite degenerate, and Ag similarity, resulting in the productive triggering of a given TCR, goes beyond sequence homology (10,38,39).…”

mentioning

confidence: 99%

Bispecificity for Myelin and Neuronal Self-Antigens Is a Common Feature of CD4 T Cells in C57BL/6 Mice

Lucca

Desbois

Ramadan

et al. 2014

The recognition of multiple ligands by a single TCR is an intrinsic feature of T cell biology, with important consequences for physiological and pathological processes. Polyspecific T cells targeting distinct self-antigens have been identified in healthy individuals as well as in the context of autoimmunity. We have previously shown that the 2D2 TCR recognizes the myelin oligodendrocyte glycoprotein epitope (MOG)35–55 as well as an epitope within the axonal protein neurofilament medium (NF-M15–35) in H-2b mice. In this study, we assess whether this cross-reactivity is a common feature of the MOG35–55-specific T cell response. To this end, we analyzed the CD4 T cell response of MOG35–55-immunized C57BL/6 mice for cross-reactivity with NF-M15–35. Using Ag recall responses, we established that an important proportion of MOG35–55-specific CD4 T cells also responded to NF-M15–35 in all mice tested. To study the clonality of this response, we analyzed 22 MOG35–55-specific T cell hybridomas expressing distinct TCR. Seven hybridomas were found to cross-react with NF-M15–35. Using an alanine scan of NF-M18–30 and an in silico predictive model, we dissected the molecular basis of cross-reactivity between MOG35–55 and NF-M15–35. We established that NF-M F24, R26, and V27 proved important TCR contacts. Strikingly, the identified TCR contacts are conserved within MOG38–50. Our data indicate that due to linear sequence homology, part of the MOG35–55-specific T cell repertoire of all C57BL/6 mice also recognizes NF-M15–35, with potential implications for CNS autoimmunity.