Scientific Report 2005

Immunology

Autoimmune Mechanisms and Compensatory Responses

N. Sarvetnick, M. Cleary, S. Dabernat, D. Dietz, C. Fine, N. Hill, H. Hua, A. Ilic, H.-B. Jie, V. Judkowski, A. Kayali, C. King, M. Kritzik, X. Li, G. Liu, A. Maday, A. Marleau, E. Rodriguez, P. Secrest, M. Solomon, L. Sterling, A. Stotland, W. Wu, D. Yadav, Y.Q. Zhang

Infection with coxsackievirus is associated with the development of autoimmunity in humans, and infection with the CB4 strain of this virus is strongly linked to the development of type 1 diabetes mellitus. However, the development of autoimmunity in general depends on the availability of autoimmune T cells in the periphery. Normally, autoreactive T cells are deleted during negative selection in the thymus, and few T cells with high affinity for self-antigens gain access to the body. We tested the hypothesis that CB4 infection inhibits negative selection in the thymus, allowing the maturation of self-reactive T cells and migration of the cells into the periphery.

We found that novel central tolerance mechanisms are responsible for coxsackievirus-induced autoimmunity. We have now determined the role of coxsackievirus in the generation of an autoimmune T-cell repertoire. Recently, we found that CB4 infects the thymus. We extended this observation to show that productive infection leads to dramatic changes in the developmental processes that occur during T-cell differentiation in the thymus. In investigating this novel aspect of virus-induced autoimmunity, we determined that CB4 infection inhibits the negative selection of self-reactive T cells in the thymus.

On the basis of our recent data, we selected several interesting mechanisms for further study. We are using a diversified molecular approach to gain information that will bring a novel mechanism linking virus infection with autoimmunity into focus, fueling new directions in therapy for virus-induced autoimmunity.

The cytokines IFN-γ and TNF-α play major roles in the destruction of pancreatic islets during the development of diabetes and in the acute rejection of islet tissue allografts. The protein termed suppressor of cytokine signaling-1 (SOCS-1) negatively regulates interferon signaling by inhibiting activation of the proteins Janus kinase and signal transducer and activator of transcription. We investigated whether modulation of interferon signaling by SOCS-1 could prevent the destruction of pancreatic islet tissue allografts in mice.

We found that islets expressing SOCS-1 that were transplanted beneath the kidney capsule of MHC-mismatched recipient mice had delayed allograft rejection and reversed streptozotocin-induced diabetes for at least 2 weeks longer than did normal islets. Surprisingly, although SOCS-1 negatively regulates interferon signaling, the islets expressing SOCS-1 responded to stimulation with IFN-γ and upregulated class I MHC self-antigens, suggesting that this negative regulation was not a factor in improved islet allograft survival. Islets expressing SOCS-1 were significantly more resistant than normal islets to cytokine-induced cell death after treatment with TNF-α alone or with TNF-α plus IFN-γ. Protection against cytokine-induced cytotoxic effects correlated with degradation of the IκB inhibitor of the upstream transcription factor NF-κB and inhibition of the transcription factor interferon regulatory factor-1, reflecting enhanced NF-κB–regulated cell survival signals. Our findings indicate that intragraft expression of SOCS-1 makes islets insensitive to the deleterious effects of cytokines and will be important in the development of therapies to prevent acute allograft rejection.

Activins regulate the growth and differentiation of a variety of cells. During the development of islets in the pancreas, activins are required for the specialization of pancreatic precursors from the gut endoderm during midgestation. We probed the role of activin signaling during the development and regeneration of pancreatic islet cells. We found that both activins and activin receptors are upregulated in duct epithelial cells during islet differentiation. Interestingly, the expression of endogenous cellular inhibitors of activin signaling, follistatin and Cripto, were also augmented. Inhibition of activins significantly enhanced survival and expansion of pancreatic epithelial cells but decreased the numbers of differentiated cells. Our results suggest that the homeostasis of growth and terminal differentiation requires a precise context-dependent regulation of activin signaling. Follistatin participates in this process by promoting proliferation of precursor cells during pancreas growth.

Publications

Jie, H.-B., Sarvetnick, N. The role of NK cells and NK cell receptors in autoimmune disease. Autoimmunity 37:147, 2004.

Judkowski, V., Rodriguez, E., Pinilla, C., Masteller, E., Bluestone, J.A., Sarvetnick, N., Wilson, D.B. Peptide specific amelioration of T cell mediated pathogenesis in murine type 1 diabetes. Clin. Immunol. 113:29, 2004.

Judkowski, V., Allicotti, G.M., Sarvetnick, N., Pinilla, C. Peptides from common viral and bacterial pathogens can efficiently activate diabetogenic T-cells. Diabetes 53:2301, 2004.

Yadav, D., Judkowski, V., Flodstrom-Tullberg, M., Sterling, L., Redmond, W.L., Sherman, L., Sarvetnick, N. B7-2 (CD86) controls the priming of autoreactive CD4 T cell responses against pancreatic islets. J. Immunol. 173:3631, 2004.

Zhang, Y.-Q, Cleary, M.M., Si, Y., Liu, G.. Eto, Y., Kritzik, M., Dabernat, S., Kayali, A.G., Sarvetnick, N. Inhibition of activin signaling induces pancreatic epithelial cell expansion and diminishes terminal differentiation of pancreatic beta-cells. Diabetes 53:2024, 2004.