Scientific Report 2005

Immunology

T-Cell Specificity and the Thymus

J. Sprent, O. Boyman, J.-H. Cho, N. Ishimaru, M. Kovar, M.P. Rubinstein

Mature T cells arise in the thymus through a process of positive and negative selection directed to MHC molecules complexed with self-peptides. In the secondary lymphoid tissues, T cells survive for prolonged periods through covert signaling elicited by interaction with self-peptide–MHC complexes and various cytokines. Contact with complexes composed of foreign peptide and MHC molecules causes
T cells to proliferate and differentiate into effector cells, with subsequent production of small numbers of memory cells.

Stimulation of Naive CD8⁺ T Cells by Fragments of Antigen-Presenting Cells

Typical immune responses of naive CD8⁺ T cells are stimulated by foreign peptide–MHC complexes on viable antigen-presenting cells (APCs) such as dendritic cells and take place in the T-dependent areas of the lymphoid tissues. Under certain conditions, however, CD8⁺ cells can respond to small membrane vesicles (exosomes) secreted by APCs. In addition, CD8⁺ cells can be stimulated by fragments of plasma membranes derived from sonicated APCs. These membrane fragments can be directly immunogenic for purified naive CD8⁺ T cells in the absence of APCs, but only when the fragments express specific peptide-MHC complexes and also coexpress both B7 and intracellular adhesion molecule 1 (the ligands for CD28 and lymphocyte function–associated antigen 1, respectively). Membrane fragments from APCs are also immunogenic in vivo and can be used to prime mice for tumor rejection.

Cytokine Control of CD8⁺ T Memory Cells

CD8⁺ T memory cells are kept alive and divide intermittently through contact with cytokines, especially IL-15. Another cytokine, IL-2, can have a negative effect on CD8⁺ memory cells, as indicated by the finding that the number of CD8⁺ memory cells are greatly increased in mice that lack IL-2 or components of the receptor for IL-2 such as CD25 (IL-2Rα) and CD122 (IL-2/IL-15Rβ). Unexpectedly, we found massive proliferation of normal CD8⁺ memory cells after the cells were transferred to mice that lack the gene for IL-2 or the gene for the IL-2 receptor. Why CD8⁺ memory cells proliferate under these conditions is unclear.

Influence of NF-κ B on T-cell Proliferation

Stimulation of T cells and other lymphoid cells is controlled by heterodimers of NF-κB1 (p50) and NF-κB2 (p52) bound to RelA and RelB subunits, respectively. In the case of NF-κB2, activation and nuclear translocation are under the control of NF-κB–inducing kinase, which is mutated in aly/aly mice. Confirming the results of others, we found that unseparated aly/aly CD4⁺ T cells have poor proliferative responses, implying an important role for NF-κB2 in proliferation. Surprisingly, however, quite different results occur when CD4⁺ T cells are separated into purified subsets of naive (CD44^lo) and memory (CD44^hi) phenotype cells. Thus, CD44^lo cells have enhanced proliferative responses and IL-2 synthesis, whereas CD44^lo cells have reduced responses. Significantly, inhibition occurs when CD44^hi cells are added to CD44^lo cells. These findings indicate that primary responses of T cells can be negatively influenced by NF-κB2.

Publications

Ganesh, K.A., Thomas, S., Thompson, L., Sprent, J., Murali-Krishna, K. Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection. J. Exp. Med., in press.

Goodnow, C.C., Sprent, J., de St. Groth, B.F., Vinuesa, C.G. Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature. 435:570, 2005.

Sprent, J. Direct stimulation of naive T cells by antigen-presenting cell vesicles. Blood Cells Mol. Dis. 35:17, 2005.

Sprent, J. Proving negative selection in the thymus. J. Immunol. 174:3841, 2005.

Sprent, J. Swapping molecules during cell-cell interactions. Sci. STKE pe8, 2005, March 1 issue.

Surh, C.D., Sprent, J. Regulation of mature T cell homeostasis. Semin. Immunol. 17:183, 2005.