Antoine Perchellet

Viral infection triggers central nervous system autoimmunity via activation of CD8 + T cells expressing dual TCRs

Multiple sclerosis is an inflammatory, demyelinating, central nervous system disease mediated by myelin-specific T cells. Environmental triggers that cause the breakdown of myelin-specific T cell tolerance are unknown. Here we found that CD8+ myelin basic protein (MBP)-specific T cell tolerance was broken and autoimmunity was induced by infection with a virus that did not express MBP cross-reactive epitopes and did not depend on bystander activation. Instead, the virus activated T cells expressing dual T cell antigen receptors (TCRs) that were able to recognize both MBP and viral antigens. Our results demonstrate the importance of dual TCR–expressing T cells in autoimmunity and suggest a mechanism by which a ubiquitous viral infection could trigger autoimmunity in a subset of infected people, as suggested by the etiology of multiple sclerosis.

CD8 + T cells maintain tolerance to myelin basic protein by 'epitope theft'

Myelin basic protein–specific CD8+ T cells can induce central nervous system autoimmunity; however, immune tolerance prevents these autoreactive cells from causing disease. To define the mechanisms that mediate tolerance, we developed two T cell receptor–transgenic mouse lines with different affinities for the H-2Kk-restricted myelin basic protein epitope consisting of amino acids 79–87 (MBP(79–87)). We observed both thymic deletion and peripheral tolerance in the lower-affinity T cells. The higher-affinity T cells, however, showed no evidence of tolerance induction and were able to prevent tolerance of the lower-affinity T cells by removing H-2Kk–MBP(79–87) complexes from antigen-presenting cells without proliferating. This form of immune regulation could limit responses of self-reactive T cells that escape other tolerance mechanisms.

The Role of CD8+ T Cells in Multiple Sclerosis and its Animal Models

The role of CD8(+) T cells in multiple sclerosis (MS) and its animal models has been enigmatic. Most studies of MS have focused on the role of CD4(+) Th1 T cells and many therapeutic strategies have been directed toward ameliorating the activity of this subset. Some of these strategies were effective in experimental autoimmune encephalomyelitis (EAE), a widely used animal model for MS dependent on CD4(+) T cells, but paradoxically have worsened disease in MS patients. A great deal of evidence suggests that CD8(+) T cells contribute to the pathogenesis of MS and should be considered in designing therapies. CD8(+) T cells outnumber CD4(+) T cells in MS lesions, and both clonal expansion and enrichment of memory cells is preferentially seen in the CD8(+) T cell subset in the brain and cerebrospinal fluid of MS patients. New animal models have been developed that employ myelin-specific CD8(+) T cells to induce central nervous system autoimmunity. In a CD8(+) T cell model targeting myelin basic protein, clinical signs and pathology distinct from CD4(+) T cell-mediated disease were observed that exhibited similarities to some aspects of MS. These differences are consistent with distinct effector mechanisms employed by CD8(+) and CD4(+) T cells in mediating tissue damage and suggest a need to consider the activity of CD8(+) T cells in drug design. This review will focus on our current understanding of the role of CD8(+) T cells in MS and the new animal models that allow us to investigate further the pathogenicity of this subset.

B7 Family Molecules as Regulators of the Maternal Immune System in Pregnancy

Citation Petroff MG, Perchellet A. B7 family molecules as regulators of the maternal immune system in pregnancy. Am J Reprod Immunol 2010

Immune tolerance to myelin proteins

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system. It is believed to be an autoimmune disease arising from a breakdown of immune tolerance in T cells specific for myelin antigens. The heterogeneity in clinical signs and pathology observed in MS patients suggests a complex pathogenesis in which the specificity of the pathogenic T cells and the tolerance mechanisms that are compromised vary among individual patients. In this review, we summarize some of the features of the diverse immune pathology observed in MS and the animal models used to study this disease. We then describe the current state of knowledge regarding the expression of the major myelin protein antigens believed to be targeted in MS and the mechanisms of immune tolerance that operate on T cells that recognize these antigens.

Endogenous Myelin Basic Protein Is Presented in the Periphery by Both Dendritic Cells and Resting B Cells with Different Functional Consequences

Multiple sclerosis is an inflammatory disease believed to be triggered by erroneous activation of self-reactive T cells specific for myelin proteins such as myelin basic protein (MBP). Inflammation is limited to the CNS, suggesting that the myelin-specific T cells encounter their Ags only after they cross the blood-brain barrier. However, our previous studies in mice showed that MBP epitopes are constitutively presented in lymphoid tissues. Here we identified which APCs in lymph nodes present endogenous MBP epitopes and determined the functional consequences of this presentation for both naive and activated MBP-specific T cells. Both CD8α+ and CD8α− dendritic cells were potent stimulators of proliferation for both naive and previously activated/memory MBP-specific T cells. Surprisingly, resting B cells also presented endogenous MBP that was acquired using a BCR-independent mechanism. Interaction with resting B cells triggered proliferation of both naive and activated MBP-specific T cells. Activated/memory MBP-specific T cells proliferating in response to resting B cells presenting endogenous MBP did not produce cytokines and became more refractory to subsequent stimulation. Interestingly, cytokine production by activated/memory T cells was triggered by resting B cells if the number of MBP epitopes presented was increased by adding exogenous MBP peptide. These results suggest that activated MBP-specific T cells may become less pathogenic in vivo following encounter with resting B cells presenting steady-state levels of endogenous MBP but can expand and remain pathogenic if the amount of MBP presented by B cells is increased, which could occur during chronic demyelinating disease.

Crosspresentation by nonhematopoietic and direct presentation by hematopoietic cells induce central tolerance to myelin basic protein

Central tolerance plays a critical role in eliminating self-reactive T cells specific for peripheral antigens. Here we show that central tolerance of MHC class I-restricted T cells specific for classic myelin basic protein (MBP), a component of the myelin sheath, is mediated by both bone marrow (BM)-derived and nonBM-derived cells. Unexpectedly, BM-derived cells induce tolerance directly by using classic MBP that they synthesize, whereas nonBM-derived cells mediate tolerance by crosspresenting classic MBP acquired from an exogenous source. Thus, tolerance to tissue-specific antigens can involve multiple cell types and mechanisms in the thymus, which may account for the limited spectrum of autoimmune syndromes observed when expression of tissue-specific antigens is impaired only in thymic epithelial cells.

Maternal CD4+ and CD8+ T Cell Tolerance Towards a Fetal Minor Histocompatibility Antigen in T Cell Receptor Transgenic Mice

ABSTRACT Tolerance of the maternal immune system in pregnancy is important for successful pregnancy because the semiallogeneic fetus may be subject to antifetal responses. We examined maternal tolerance to the fetus using a murine system in which a model paternally inherited antigen, ovalbumin (OVA), is expressed exclusively in the fetus and placenta. By employing T cell receptor (TCR) transgenic mice specific for major histocompatibility complex class I- or class II-restricted epitopes of OVA (OT-I and OT-II) as mothers, we investigated the fate of fetus-specific CD8+ and CD4+ T cells, respectively, during gestation. Both OVA-specific CD8+ and CD4+ T cells displayed an activated phenotype in the peripheral lymphoid tissues of OVA-bred OT-I and OT-II mice, consistent with their encounter of fetal antigen. Whereas a small percentage of OVA-specific CD4+ T cells were deleted in the periphery and thymus of OVA-bred OT-II mice, with evidence of TCR downregulation in the remaining T cells, deletion and TCR downregulation were not observed in OVA-bred OT-I mice. Both CD4+ and CD8+ T cells upregulated inducible costimulator expression in response to the fetal antigen, but only CD4+ T cells consistently upregulated the inhibitory receptors programmed cell death 1 and cytotoxic T lymphocyte antigen-4. More regulatory T cells (Tregs) were present in pregnant OVA-bred than in WT-bred OT-II mice, revealing that Tregs expanded specifically in response to the fetal antigen. These data indicate that several mechanisms tolerize fetal antigen-specific maternal CD4+ T cells, whereas tolerance of fetal antigen-specific CD8+ T cells is less effective. The importance of these mechanisms is underscored by the finding that fetal loss occurs in OVA-bred OT-I but not OT-II mice.

REVIEW ARTICLE: B7 Family Molecules as Regulators of the Maternal Immune System in Pregnancy

Citation Petroff MG, Perchellet A. B7 family molecules as regulators of the maternal immune system in pregnancy. Am J Reprod Immunol 2010

B7 Family Molecules as Regulators of the Maternal Immune System in Pregnancy: B7 FAMILY MOLECULES IN REPRODUCTION

Citation Petroff MG, Perchellet A. B7 family molecules as regulators of the maternal immune system in pregnancy. Am J Reprod Immunol 2010