Alexander Chervonsky, M.D., Ph.D.

Homing of Autoimmune T Cells to Targeted Tissues, Selection of T Cells with Autoimmune T Cells in the Thymus, and the Role of Innate Immune Mechanisms in Development of Organ-Specific Autoimmnunity, such as Type 1 diabetes

Research Summary

Pathogenesis of autoimmune diseases is extremely complex. We are interested in organ-specific diseases such as autoimmune diabetes and psoriasis, and we have mouse models for both. Our studies focus on determining how T cells are initially activated in disease pathogenesis, how they home to the target organs, and how they destroy these organs.

We have found that aberrant positive selection of T cells is involved in autoimmunity. The role of this process in autoimmunity is addressed using transgenic mouse models. T cell receptors (TCRs) with an unusual feature—the ability to interact with both major histocompatibility complex (MHC) class I and MHC class II molecules—are being studied. Such T cells are common in mice with a limited diversity of MHC molecules and a limited diversity of peptides bound to the MHC. One such TCR, MM14.4, when expressed as a transgene, causes skin lesions most closely resembling human psoriasis. T cells carrying the MM14.4 TCR are selected into both CD4+ and CD8+ T cell subsets. Other dual-restricted receptors have been cloned, and additional transgenic mice carrying such receptors have been generated and are being analyzed.

Using a mouse model for autoimmune diabetes, we have started a new project to investigate the involvement of innate Toll-like receptors (TLRs) in autoimmunity. TLRs are involved in responses to infection with pathogens, but also maybe involved in the activation of non-infectious immunity. These studies will help to solve the longstanding riddle of how infection with pathogens is connected to autoimmunity.

To address the issue of the homing of effector T cells to their targets, we used insulin-specific CD8+ T cells (IS-CD8+). Homing is a multi-step process that involves increased adhesion between T cells and endothelial cells and subsequent extravasation (diapedesis). Our studies of the molecular mechanisms of IS-CD8+ cell trafficking to the islets have revealed a specific chemokine, CCL21, participating in firm adhesion. Using a genetic approach, we obtained new gene expression data on molecules involved in T cell homing to the pancreas. Analysis of changes in gene expression in the pancreas from mice treated with interferon gamma revealed that several chemokines were upregulated in response to such treatment. The role of these chemokines in the extravasation of islet-specific T lymphocytes is being studied. In addition, we determined that homing of IS-CD8+ cells to the pancreas is controlled genetically, and that some mouse strains do not support homing of IS-CD8+ cells. We are currently studying the underlying mechanisms, an understanding of which would allow us to suggest new therapeutic measures to stop the trafficking of auto-aggressive T cells to their targets.

We are also interested in how T cells that have reached their targets destroy them. We have been focusing on the Fas-mediated pathway of induced cell death. We previously determined that pancreatic ß cells can express Fas under the influence of as yet unknown signals from infiltrating T cells. We have now identified the nature of the signal. We have also generated mice with a conditional knock-out of Fas in ß cells, and we are studying diabetogenesis in these mice under conditions when Fas is permanently removed from ß cells during pathogenesis.
Another project deals with development and function of specialized epithelial cells, termed M cells. M cells are necessary for transepithelial transport of microbes for the purpose of probing the microflora for the presence of pathogens, and are closely associated with B lymphocytes. While studying the role of factors in the Tumor Necrosis Family most commonly involved in organogenesis, we found that production of these factors by B cells was completely dispensable for M cell generation. Studies of other signaling pathways potentially involved in molecular conversation between B and M cells are in progress.

Selected Papers

Chervonsky AV, Gordon L, Sant AJ. (1994). A segment of the MHC Class II beta chain plays a critical role in targeting Class II molecules to the endocytic pathway. Int Immunol 6:973-982.

Chervonsky AV, Sant AJ. (1995). In the absence of MHC class II molecules, invariant chain is translocated to late endocytic compartments by autophagy. Eur J Immunol 25:911-918.

Chervonsky AV, Xu J, Barlow AK, Khery M, Flavell RA, Janeway Jr. CA. (1995). Direct, physical interaction involving CD40 ligand on T-cells and CD40 on B cells is required to propagate MMTV. Immunity 3:139.

Chervonsky AV, Wang Y, Wong FS, Visintin I, Flavell RA, Janeway Jr CA, Matis LA. (1997). The role of Fas in autoimmune diabetes. Cell 89:17-24.

Chervonsky AV, Medzhitov RM, Denzin LK, Barlow AK, Rudensky AY, Janeway Jr CA. (1998). Subtle conformational changes induced in major histocompatibility complex class II molecules by binding peptides. Proc Natl Acad Sci USA 95:10094-10099.

Chervonsky AV. (1999). Apoptotic and effector pathways in autoimmunity. Curr Opin Immunol 11:684-688.

Golovkina T, Shlomchik M, Hannum L, Chervonsky A. (1999). Organogenic role of B lymphocytes in mucosal immunity. Science 286(5446):1965-1968.

Golovkina TV, Agafonova Y, Kazansky D, Chervonsky AV. (2001). Diverse repertoire of the MHC class II-peptide complexes is required for presentation of viral superantigens. J Immunol 166:2244-2250.

Savinov A, Wong SF, Chervonsky A. (2001). IFN-gamma affects homing of diabetogenic T cells. J Immunol 167:6637-6643.

Jude BA, Pobezinskays Y, Parke S, Medzhitov RM, Chervonsky AV, Golovkina TV. (2003). Subversion of the innate immune system by a retrovirus. Nature Immunol 4:573-578.

Savinov A, Tcherepanov A, Green EA, Flavell RA, Chervonsky A. (2003). Contribution of Fas to diabetes development. Proc Natl Acad Sci USA, 100:626-632.
Savinov A., Wong SF, Stonebraker A, Chervonsky A. (2003). Cross-presentation of antigen by endothelial cells and chemoattraction are required for homing of insulin-specifc CD8+ T cells. J Exp Med, 197:643-656.

Tumanov A, Kuprash DV, Mach JA, Nedospasov SA, Chervonsky A. (2004). Lymphotoxin and TNF produced by B cells are dispensable for maintenance of the follice-associated epithelium but are required for development of lymphoid follicles in the Peyer's pathces. J Immunol 173:86-91.

Logunova NN, Viret C, Pobezinsky LA, Miller SA, Kazansky DB, Sundberg JP, Chervonsky AV. (2005). Restricted MHC-peptide repertoire predisposes to autoimmunity. J Exp Med 202(1):73-84.

Mach J, Hshieh T, Hsieh D, Grubbs N, Chervonsky A. (2005). Development of intestinal M cells. Immunol Rev 206:177-189

Stranges PB, Watson J, Cooper CJ, Choisy-Rossi CM, Stonebraker AC, Beighton RA, Hartig H, Sundberg JP, Servick S, Kaufmann G, Fink PJ, Chervonsky AV. (2007). Elimination of antigen-presenting cells and autoreactive T cells by fas contributes to prevention of autoimmunity. Immunity. 26(5):629-41. PMID: 17509906

Wen, L. ,  Ley, R.E, Volchkov, P.U., Stranges, B.P., Avanesyan, L., Stonebraker, A.C.,  Hu, C.,,  Wong, F.S.,  Szot, G.L.,, Bluestone, J.A., Gordon, J.I  & Chervonsky, A.V., (2008), Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature, 23:1109-13.