News and Publications

Selection of the T-Cell Repertoire

C.D. Surh, D.-S. Lee, B.B. Ernst, E. Leroy, K. Vuu, J. Min, J. Lee, C. Ahn*

* Seoul National University Hospital, Seoul, Korea

The mature T-cell repertoire is generated in the thymus through a combination of positive and negative selection directed against complexes composed of self-peptides and MHC molecules that are expressed on epithelial cells and on antigen-presenting cells. We are interested in deciphering the role of self-peptides in the generation of T cells in the thymus and in the maintenance of these T cells in the extrathymic environment.

ROLE OF SELF-PEPTIDES IN T-CELL SELECTION IN THE THYMUS

T cells normally develop in the thymus by contacting self-MHC molecules loaded with a wide spectrum of self-peptides. To investigate the contribution of each distinct MHC-peptide complex to the selection of the mature T-cell repertoire, we studied the repertoire and function of CD4⁺ T cells from H2-M--deficient mice. These mice express normal levels of MHC class II molecules that are loaded virtually with only a single peptide, the class II--associated invariant chain peptide (CLIP).

Despite expressing only 1 species of MHC-peptide complexes, H2-M--deficient mice have considerable numbers (20--50% of normal) of polyclonal CD4⁺ cells. However, because these cells have not encountered non-CLIP self-peptides during tolerance induction, the majority of the cells react strongly to wild-type syngeneic antigen-presenting cells and can induce graft-versus-host disease when transferred to other mice. Surprisingly, however, H2-M--deficient mice do not reject wild-type syngeneic skin grafts, even though they rapidly reject third-party grafts. Such split-tolerance may indicate that the reactivity of CD4⁺ cells from H2-M--deficient mice for wild-type antigen-presenting cells is controlled by low-affinity cells, because high-affinity cells have been deleted. Production of high-affinity T cells specific to non-self peptides thus may require thymic selection against a multitude of self-peptides expressed at low density.

ROLE OF SELF-PEPTIDES IN T-CELL SURVIVAL IN THE PERIPHERY

In order to receive covert signals that maintain their survival, mature T cells in the peripheral lymphoid tissues require continuous contact with antigen-presenting cells expressing self-MHC molecules. Recently, we found that recognition of self-MHC molecules for T-cell survival is not peptide blind; rather, it depends on the recognition of specific self-peptides. Thus, CD4⁺ cells that have matured in the presence of particular self-peptides in the thymus do not persist when adoptively transferred into MHC-matched secondary hosts that do not express the same peptides. We hypothesize that survival of mature T cells in the extrathymic environment requires continuous contact with the self-peptides the cells originally encountered during positive selection in the thymus.

PUBLICATIONS

Kishimoto, H., Surh, C.D., Sprent, J. A role for Fas in negative selection of thymocytes in vivo. J. Exp. Med. 187:1427, 1998.

Liljedahl, M., Winqvist, O., Surh, C.D., Wong, P., Ngo, K., Teyton, L., Peterson, P.A., Brunmark, A., Rudensky, A.Y., Fung-Leung, W.P., Karlsson, L. Altered antigen presentation in mice lacking H2-O. Immunity 8:233, 1998.

Surh, C.D., Kosaka, H., Sprent, J. Rat stem cells developing in irradiated SCID mice fail to become tolerized and cause lethal graft-versus-host disease. Am. J. Pathol. 151:591, 1997.

Surh, C.D., Lee, D.-S., Fung-Leung, W.-P., Karlsson, L., Sprent, J. Thymic selection by a single MHC/peptide ligand produces a semi-diverse repertoire of CD4⁺ T cells. Immunity 7:209, 1997.

Surh, C.D., Sprent, J. The thymus and T cell development. In: Inflammation: Basic Principles and Clinical Correlates. Gallin, J.I., et al. (Eds.). Lippincott-Raven, Philadelphia, in press.