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Viruses can cause but can also prevent autoimmune disease. This dualism has certainly hampered attempts to establish a causal relationship between viral infections and type 1 diabetes (T1D). To develop a better mechanistic understanding of how viruses can influence the development of autoimmune disease, we exposed prediabetic mice to various viral infections. We used the well-established NOD and transgenic RIP-LCMV models of autoimmune diabetes. In both cases, infection with the lymphocytic choriomeningitis virus (LCMV) completely abrogated the diabetic process. Interestingly, such therapeutic viral infections resulted in a rapid recruitment of T lymphocytes from the islet infiltrate to the pancreatic draining lymph node, where increased apoptosis was occurring. In both models this was associated with a selective and extensive expression of the chemokine IP-10 (CXCL10), which predominantly attracts activated T lymphocytes, in the pancreatic draining lymph node, and in RIP-LCMV mice it depended on the viral antigenic load. In RIP-LCMV mice, blockade of TNF-alpha or IFN-gamma in vivo abolished the prevention of T1D. Thus, virally induced proinflammatory cytokines and chemokines can influence the ongoing autoaggressive process beneficially at the preclinical stage, if produced at the correct location, time, and levels.

In vitro PA28 binds and activates proteasomes. It is shown here that mice with a disrupted PA28b gene lack PA28a and PA28b polypeptides, demonstrating that PA28 functions as a hetero-oligomer in vivo. Processing of antigenic epitopes derived from exogenous or endogenous antigens is altered in PA28$^{-/-}$ mice. Cytotoxic T lymphocyte responses are impaired, and assembly of immunoproteasomes is greatly inhibited in mice lacking PA28. These results show that PA28 is necessary for immunoproteasome assembly and is required for efficient antigen processing, thus demonstrating the importance of PA28-mediated proteasome function in immune responses.

Minimal Impact of a De Novo–Expressed β-Cell Autoantigen on Spontaneous Diabetes Development in NOD Mice Marianne M. Martinic 1 , Amy E. Juedes 1 , Damien Bresson 1 , Dirk Homann 2 , Kresten Skak 3 , Christoph Huber 4 , Eleanor Ling 1 , Mette Ejrnaes 1 , Tom Wolfe 1 , Lisa Togher 1 , Urs Christen 5 and Matthias G. von Herrath 1 1 Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California 2 Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 3 Pharmacology Research, Novo Nordisk A/S, Måløv, Denmark 4 Department of Immunology, The Scripps Research Institute, La Jolla, California 5 Klinik der Johann Wolfgang Goethe Universität, Frankfurt, Germany Address correspondence and reprint requests to Marianne M. Martinic or Matthias G. von Herrath, Immune Regulation Lab DI-3, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037. E-mail: marmar{at}liai.org or matthias{at}liai.org Abstract During an autoimmune process, the autoaggressive response spreads from the initiating autoantigen to other antigens expressed in the target organ. Based on evidence from experimental models for multiple sclerosis, such “antigenic spreading” can play an important role in the exacerbation of clinical disease. We evaluated whether pathogenesis of spontaneous diabetes in NOD mice could be accelerated in a similar way when a novel autoantigen was expressed in pancreatic β-cells. Unexpectedly, we found that the expression of the lymphocytic choriomeningitis virus nucleoprotein only led to marginal enhancement of diabetes, although such NOD-nucleoprotein mice were not tolerant to nucleoprotein. Although the frequency of nucleoprotein-specific CD8 T-cells in the pancreatic draining lymph node was comparable with the frequency of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific T-cells, more IGRP-specific CD8 T-cells were found both systemically and in the islets where there was a fourfold increase. Interestingly, and in contrast to nucleoprotein-specific CD8 T-cells, IGRP-specific T-cells showed increased CXCR3 expression. Thus, autoreactivity toward de novo–expressed β-cell autoantigens will not accelerate autoimmunity unless large number s of antigen-experienced autoreactive T-cells expressing the appropriate chemokine receptors are present. CTL, cytotoxic T-lymphocyte CNS, central nervous system EAE, experimental autoimmune encephalomyelitis ELISA, enzyme-linked immunosorbent assay GAD, glutamic acid decarboxylase HBS, hepatitis B virus polyadenylation signal IFN-γ, γ-interferon IGRP, islet-specific glucose-6-phosphatase catalytic subunit-related protein IL, interleukin LCMV, lymphocytic choriomeningitis virus MHC, major histocompatibility complex PBS-T, 0.05% Tween 20 in PBS PDLN, pancreatic draining lymph node pfu, plaque forming unit RIP, rat insulin promoter Footnotes M.M.M. and A.E.J. contributed equally to this work. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted November 22, 2006. Received January 14, 2005. DIABETES

A long-standing paradox in cellular immunology concerns the conditional requirement for CD4 + T-helper (T H ) cells in the priming of cytotoxic CD8 + T lymphocyte (CTL) responses in vivo . Whereas CTL responses against certain viruses can be primed in the absence of CD4 + T cells, others, such as those mediated through ‘cross-priming’ by host antigen-presenting cells, are dependent on T H cells 1 , 2 , 3 , 4 . A clearer understanding of the contribution of T H cells to CTL development has been hampered by the fact that most T H -independent responses have been demonstrated ex vivo as primary cytotoxic effectors, whereas T H -dependent responses generally require secondary in vitro re-stimulation for their detection. Here, we have monitored the primary and secondary responses of T H -dependent and T H -independent CTLs and find in both cases that CD4 + T cells are dispensable for primary expansion of CD8 + T cells and their differentiation into cytotoxic effectors. However, secondary CTL expansion (that is, a secondary response upon re-encounter with antigen) is wholly dependent on the presence of T H cells during, but not after, priming. Our results demonstrate that T-cell help is ‘programmed’ into CD8 + T cells during priming, conferring on these cells a hallmark of immune response memory: the capacity for functional expansion on re-encounter with antigen.