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Suicide or second chance

How the body responds to autoimmune T cells

Munich, 05/04/2010

T cells form a crucial part of the human immune system. They develop in the thymus and each T cell expresses a unique receptor on its surface. The enormous diversity of these receptors is what makes the T cell population capable of recognizing and inactivating essentially all pathogenic entities with which it might be confronted. But the repertoire of T cells in the thymus includes autoreactive cells that have the potential to bind to molecular structures on the body’s own tissues. If such cells are not removed or neutralized, autoimmune diseases like Type-1 diabetes, multiple sclerosis or Crohn’s disease may develop. A team of researchers led by LMU immunologist Professor Ludger Klein, in collaboration with investigators at TU München, has now elucidated new aspects of how these dangerous T cells are detected and eliminated before they can leave the thymus. “We also discovered why some of these T cells are driven to self-destruct, while others are ‘re-educated’ to become so-called regulatory T cells”, reports Klein. “We hope that the results will improve our understanding of autoimmune diseases, and perhaps provide a point of departure for innovative therapeutic approaches.” (Nature Immunology online, 2 May 2010)

B and T lymphocytes, which belong to the class of white blood cells, form the two arms of the adaptive immune system. B cells fight extracellular pathogens. T cells use specific binding proteins on their surfaces, called T-cell receptors (TCRs), to recognize cells infected by intracellular parasites. The precursors of T cells reside in the bone marrow, but migrate to the thymus to differentiate. Here each T-cell acquires the capacity to express a single type of TCR. The TCR is the product of a gene that has undergone a random rearrangement, so each TCR is essentially unique to a single cell. Inevitably some T cells will have TCRs that can bind to “self antigens” – proteins that are normally present in the body’s own cells. “Potentially dangerous T cells that bind self antigens are targeted for inactivation or elimination, usually in the thymus itself”, says LMU immunologist Ludger Klein. “They either undergo programmed cell death (apoptosis) or are ‘re-educated’ to become regulatory T cells. The latter can still recognize self structures, but they now function to keep other deleterious T cells in check.“

Several years ago Klein and his coworkers showed that specialized cells in the thymus, called medullary thymic epithelial cells (mTECs), express a large pool of self antigens that are otherwise restricted to differentiated cell types in peripheral tissues. These proteins are cut into short peptide fragments by enzymes, and ferried to the cell surface by so-called MHC proteins (products of the Major Histocompatibility Complex), making them “visible” to T cells. “In a sense, the medullary epithelium produces an image of the body’s antigenic landscape”, explains Maria Hinterberger, lead author of the new study, “allowing T cells that recognize self antigens to be identified and deleted in the thymus.” However, whether mTECs can efficiently present antigens to T cells has been unclear. “It has been suggested that the peptide fragments are produced by mTECs and subsequently captured and presented by dendritic cells (another type of lymphoid cell) in the thymus”, says Hinterberger. “In our new work, we asked whether the mTECs themselves act as antigen-presenting cells.“

Hinterberger and her colleagues used a genetic trick, the “knock-down” method, to reduce the levels of MHC proteins in the mTECs of mice, interfering with transport of antigen fragments to the cell surface without perturbing their production. “We found that autoreactive T cells were not efficiently eliminated by apoptosis in these mice“, says Klein, “and this result tells us that mTECs must act as antigen-presenting cells.“ Moreover, low levels of autoimmune destruction were observed in several organs in these mice, indicating that autoreactive T cells had indeed escaped from the thymus.

The study also throws light on the question of why many deleterious T cells are induced to commit suicide, while others are converted into regulatory T-cells. As its name implies, the knock-down method does not completely inactivate the genetic function targeted. In the present case, the antigen-presenting capacity of the mTECs was reduced by 90%. “As a result, some T cells that would normally have been eliminated developed into regulatory cells“, says Klein. “This observation implies that the strength of the antigen recognition reaction in the thymus determines whether a self-reactive T cell is destroyed or becomes a harmless regulatory T-cell.“ A better understanding of the mechanism of this effect may suggest ways of developing new strategies for the treatment of autoimmune diseases. (CA)

 

Publication:
“Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance”;
Maria Hinterberger, Martin Aichinger, Olivia Prazeres da Costa, David Voehringer, Reinhard Hoffmann, Ludger Klein;
Nature Immunology online; 2 May 2010;
DOI: 10.1038/ni.1874

 

Contact:
Professor Dr. Ludger Klein
Institut für Immunologie der Ludwig-Maximilians-Universität (LMU) München
Phone: +49 (0) 89 / 2180-75696
E-mail: ludger.klein@med.uni-muenchen.de
Web: http://immuno.web.med.uni-muenchen.de/020_Research/025_AG_Klein/index.html

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