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News and Publications
The Thymus and T-Cell Specificity
J. Sprent, H. Fuji, I. Hwang, A.D. Judge, H. Kishimoto, D.F. Tough*
* The Edward Jenner Institute for Vaccine Research, Berkshire, England
Differentiation of immature T cells in the thymus is guided by T-cell receptor (TCR) recognition of MHC molecules. T cells with low but significant affinity for complexes composed of self-peptide and MHC molecules are selected for survival and export to the periphery (positive selection), whereas T cells with high affinity are deleted (negative selection), thus ensuring self-tolerance. We are interested in the mechanisms involved in negative selection of immature T cells in the thymus and in the factors that control the survival and activation of mature T cells in the secondary lymphoid tissues.
NEGATIVE SELECTION IN THE THYMUS
In normal animals, intrathymic contact with ubiquitous MHC-bound peptides deletes the majority of self-reactive T cells. Tolerance to tissue-specific antigens expressed in the brain, muscle, and so forth is thought to be controlled largely by peripheral tolerance mechanisms, although minor expression of tissue-specific antigens in the thymus may induce some degree of central tolerance (negative selection) to these antigens.
Useful information on the induction of self-tolerance has come from studies in particular mouse strains in which autoimmune disease develops spontaneously, notably type 1 diabetes mellitus in nonobese diabetic (NOD) mice. Onset of disease in NOD mice is usually attributed to defects in peripheral tolerance mechanisms. However, we found that thymocytes from NOD mice have a conspicuous defect in central tolerance. Thus, in contrast to thymocytes from normal mice, thymocytes from NOD mice have impaired deletion (apoptosis) in response to TCR-CD28 ligation in vitro and poor negative selection after in vivo injection of foreign antigens. The defect in central tolerance in thymocytes from NOD mice does not apply to typical CD4+ CD8+ cortical thymocytes and is restricted to a population of semimature T cells found in the medulla. The molecular mechanisms responsible for defective negative selection in NOD mice are being examined.
SURVIVAL AND TURNOVER OF MATURE T CELLS
In young mice, a small proportion of T cells characterized by high expression of CD44 molecules (CD44hi cells) are thought to be memory cells specific for various environmental antigens. For both CD4+ and CD8+ cells, the background turnover (rate of proliferation) of memory phenotype T cells is higher than that for naive T cells, implying that memory phenotype T cells are being continuously stimulated.
For CD44hi CD8+ cells, turnover in vivo increases sharply after injection of agents that lead to the production of interferons; injection of purified interferons, either type I IFN or IFN-g, has a similar effect. Because interferons cannot induce proliferation of purified T cells in vitro, we postulated that interferon-induced T-cell proliferation in vivo is mediated by production of an additional cytokine, an effector cytokine that is directly stimulatory for CD44hi CD8+ cells.
Confirming our hypothesis that the effector cytokine is IL-15, interferon-induced proliferation of CD44hi CD8+ cells in vivo does not occur after adoptive transfer of these cells to IL-15-/- mice. Moreover, CD44hi CD8+ cells disappear rapidly in IL-15-/- hosts. These findings indicate that in vivo contact with IL-15 plays a key role in controlling both the survival and the turnover of CD44hi CD8+ cells.
T-CELL INGESTION OF MOLECULES DERIVED FROM ANTIGEN-PRESENTING CELLS
We found previously that interaction of T cells with antigen-presenting cells (APCs) causes T cells to absorb and internalize cell-surface molecules from APCs. This process is controlled by at least 2 molecules on T cells, CD28 and TCRs, and reflects binding of complementary molecules, B7 and peptide-MHC, on APCs. With the aid of various drugs, including latrunculin B, we showed that T-cell absorption and internalization of APC-derived molecules is an active process that requires the action of the cytoskeleton. We also observed that T cells can absorb APC-derived molecules in soluble form. The biological significance of this finding is being investigated.
PUBLICATIONS
Hwang, I., Sprent, J. Role of the actin cytoskeleton in T cell absorption and internalization of ligands from APC. J. Immunol. 166:5099, 2001.
Kishimoto, H., Sprent, J. A defect in central tolerance in NOD mice. Nat. Immunol., in press.
Kishimoto, H., Sprent, J. The thymus and negative selection. Immunol. Res. 21:315, 2000.
Sprent, J. Burnet Oration: T-cell survival and the role of cytokines. Immunol. Cell Biol. 79:199, 2001.
Sprent, J. IFN-dependent pathways for stimulation of memory CD8+ cells. In: Microbial DNA and Immune Modulation. Raz, E. (Ed.). Humana Press, Totowa, NJ, in press.
Sprent, J. Turnover of memory-phenotype CD8+ T cells. Microbes Infect., in press.
Sprent, J., Kishimoto, H. The thymus and central tolerance. Philos. Trans. R. Soc. Lond. B Biol. Sci. 356:609, 2001.
Sprent, J., Surh, C.D. Generation and maintenance of memory T cells. Curr. Opin. Immunol. 13:248, 2001.
Sprent, J., Surh, C.D. T-cell biology and the thymus. In: Samter's Immunologic Diseases, 6th ed., Vol. 1. Austen, F., et al. (Eds.). Lippincott Williams & Wilkins, Baltimore, 2001, p. 43.
Sprent, J., Tough, D.F. T cell death and memory. Science 293:245, 2001.
Sun, S., Zhang, X., Tough, D.F., Sprent, J. Multiple effects of immunostimulatory DNA on T cells and the role of type I interferons. Springer Semin. Immunopathol. 22:77, 2000.
Surh, C.D., Sprent, J. Homeostatic T cell proliferation. How far can T cells be activated to self-ligands? J. Exp. Med. 192:F9, 2000.
Tan, J.T., Dudl, E., LeRoy, E., Murray, R., Sprent, J., Weinberg, K.I., Surh, C.D. IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc. Natl. Acad. Sci. U. S. A. 98:8732, 2001.
Tough, D.F., Zhang, X., Sprent, J. An IFN-g dependent pathway controls stimulation of memory phenotype CD8+ T cell turnover in vivo by IL-12, IL-18, and IFN-g. J. Immunol. 166:6007, 2001.
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