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The Thymus and T-Cell Specificity

J. Sprent, H. Fujii, I. Hwang, A.D. Judge, X. Shen, D.F. Tough,* X. Zhang, H. Kishimoto

* The Edward Jenner Institute for Vaccine Research, Berkshire, England

As the result of positive and negative selection in response to self-peptide-MHC complexes in the thymus, T cells entering the peripheral lymphoid tissues are kept alive by low-level interactions between T-cell receptors and self-ligands. Mature T cells respond vigorously to foreign antigens but, through central tolerance (negative selection), are largely devoid of cells with overt autoreactivity. We are interested in the mechanisms responsible for inducing and maintaining this state of self-nonself discrimination.

NEGATIVE SELECTION IN THE THYMUS

Induction of self-tolerance is defective in certain strains of mice. For example, features of autoimmune disease, especially type 1 diabetes mellitus, develop in nonobese diabetic (NOD) mice. The predisposition of NOD mice to autoimmune disease is usually attributed to defects in peripheral tolerance mechanisms. However, we found that NOD mice have a defect in negative selection of thymocytes.

Impaired central tolerance in NOD mice is most prominent in a population of semimature thymocytes found in the medulla of the thymus. The defect is apparent both in vivo and in vitro; is independent of expression of IAb^g7, the class II MHC molecule encoded by the gene associated with susceptibility for diabetes in NOD mice; and affects both Fas-dependent and Fas-independent pathways of apoptosis. For Fas-dependent apoptosis, defective tolerance of NOD thymocytes correlated with strong T-cell receptor-mediated upregulation of cFLIP, an inhibitor of Fas-mediated apoptosis. These findings suggest that the onset of disease in NOD mice may reflect defects in both central and peripheral tolerance.

HOMEOSTASIS OF MEMORY-PHENOTYPE CD8⁺ CELLS

Previously, we found that the rate of T-cell turnover (proliferation) in vivo is faster for CD4⁺ and CD8⁺ cells with a memory (CD44^hi) phenotype than for typical naive-phenotype (CD44^lo) T cells. However, this finding applies only to young mice. We discovered that compared with young mice, aged mice had a marked reduction in turnover of T cells in vivo at the level of memory-phenotype CD44^hi CD8⁺ cells. On the basis of the results of adoptive transfer experiments, we think that the reduced turnover of CD44^hi CD8⁺ cells in aged mice reflects an inhibitory influence of the host environment in older mice. CD44^hi CD8⁺ cells from aged mice also responded poorly to IL-15 and IL-15-inducing agents in vivo but responded well to IL-15 in vitro.

Two mechanisms could account for the reduced turnover of CD44^hi CD8⁺ cells in aged mice. First, aging was associated with a prominent and selective increase in the expression of the antiapoptotic molecule Bcl-2 in CD44^hi CD8⁺ cells. Hence, the reduced turnover of CD44^hi CD8⁺ cells in aged mice may in part reflect the antiproliferative effect of enhanced Bcl-2 expression. Second, the impaired in vivo response of CD44^hi CD8⁺ cells in aged mice to IL-15 correlated with increased serum levels of type I interferons and was largely reversed by injection of antibody to type I interferons. Hence, the selective reduction in the turnover of CD44^hi CD8⁺ cells in aged mice in vivo may reflect the combined inhibitory effects of enhanced expression of Bcl-2 and high levels of type I interferons.

PUBLICATIONS

Hwang, I., Cai, Z., Sprent, J. Receptor specific T cell-absorption and internalization of ligands derived from antigen-presenting cells. In: Recent Research Developments in Immunology, Vol. 3. Pandalai, S.G. (Ed.). Research Signpost, Kerala, India, 2001, p. 161.

Judge, A.D., Zhang, X., Fujii, H., Surh, C.D., Sprent, J. Interleukin 15 controls both proliferation and survival of a subset of memory-phenotype CD8⁺ T cells. J. Exp. Med. 196:935, 2002.

Kieper, W.C., Tan, J.T., Bondi-Boyd, B., Gapin, L., Sprent, J., Ceredig, R., Surh. C.D. Overexpression of interleukin (IL)-7 leads to IL-15-independent generation of memory phenotype CD8⁺ T cells. J. Exp. Med. 195:1533, 2002.

Kishimoto, H., Sprent, J. A defect in central tolerance in NOD mice. Nat. Immunol. 2:1025, 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. T memory cells: quality not quantity. Curr. Biol. 12:R174, 2002.

Sprent, J. Turnover of memory-phenotype CD8⁺ T cells. Microbes Infect., in press.

Sprent, J., Judge, A., Zhang, X. Cytokines and memory-phenotype CD8⁺ cells. In: Proceedings of the 9th International Conference on Lymphocyte Traffic and Homeostasis. Gupta, S., Butcher, E.C., Paul, W.E. (Eds.). Kluwer Academic/Plenum, New York, in press.

Sprent, J., Kishimoto, H. The thymus and central tolerance. Transplantation 72(8 Suppl.):S25, 2001.

Sprent, J., Kishimoto, H. The thymus and negative selection. Immunol. Rev. 185:126, 2002.

Sprent, J., Surh, C.D. T cell memory. Annu. Rev. Immunol. 20:551, 2002.

Sprent, J., Uittenbogaart, C.H., Fink, P.J. A season for midwinter immunology. Nat. Immunol. 3:414, 2002.

Surh, C.D., Sprent, J. Regulation of naive and memory T-cell homeostasis. Microbes Infect. 4:51, 2002.

Tan, J.T., Ernst, B., Kieper, W.C., LeRoy, E., Sprent, J., Surh, C.D. Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8⁺ cells but are not required for memory phenotype CD4⁺ cells. J. Exp. Med. 195:1523, 2002.

Tough, D.F., Sprent, J. Immunological memory. In: Fundamental Immunology, 5th ed. Paul, W.E. (Ed.). Lippincott Williams & Wilkins, Philadelphia, in press.

Zhang, X., Fujii, H., Kishimoto, H., LeRoy, E., Surh, C.D., Sprent, J. Aging leads to disturbed homeostasis of memory-phenotype CD8⁺ cells. J. Exp. Med. 195:283, 2002.