Scientific Report 2005

Immunology

Regulation of Homeostasis of Mature T Cells

C.D. Surh, J. Tan, C. Ramsey, J. Purton, J.Y. Lee, W.C. Kieper, J.T. Burghardt, D. Kim, C. Ahn* * Seoul National University Hospital, Seoul, Korea

The pool of mature T cells is constantly regulated by homeostatic mechanisms to remain at a steady size and maintain predictable proportions of naive and memory T cells. Homeostatic signals are received as a result of interactions of T cells with self-MHC molecules and the cytokines IL-7 and IL-15. Thus, contact with self-MHC molecules and IL-7 is required for survival of naive T cells, and a combination of IL-7 and IL-15 is required for survival of memory T cells.

A hallmark of homeostatic regulation is the ability of both naive and memory T cells to undergo spontaneous homeostatic proliferation in response to severe T-cell depletion. A slower rate of homeostatic proliferation is also evident for memory T cells under normal T cell–sufficient conditions, but not for most naive T cells. Because the requirements for homeostatic proliferation closely mirror the requirements for cell survival, most likely the survival signals delivered by low levels of IL-7 and IL-15 become mitogenic signals when the concentrations of these cytokines are elevated.

Homeostatic proliferation of naive T cells is driven by signals induced by contact of the cells with low-affinity ligands composed of self-antigens, MHC molecules, and peptides that have been intensified by elevated levels of IL-7. Thus, polyclonal naive T cells transferred into syngeneic wild-type mice treated to be lymphopenic undergo mostly homeostatic proliferation as indicated by the cell division rate of 1 division every 24–36 hours. In congenitally T cell–deficient syngeneic hosts, however, a fraction of polyclonal naive T cells undergoes a prodigious rate of proliferation and outcompetes the rest of the naive cells that are undergoing slow homeostatic proliferation. Such rapid T-cell proliferation resembles proliferation driven by high-affinity foreign antigens, because the resultant T cells have characteristics of effector cells. The proliferation also occurs largely independent of homeostatic factors, that is, in the absence of IL-7 and in T cell–sufficient hosts that are nonetheless devoid of functional T-cell immunity.Consistent with the idea that foreign antigens induce such a rapid form of proliferation, congenitally immunodeficient mice raised under germ-free conditions had only slow homeostatic proliferation, not the rapid T-cell proliferation that occurred in conventionally raised immunodeficient mice. Thus, polyclonal proliferation of naive T cells in T cell–deficient hosts can be driven predominantly by either self-antigens or foreign antigens, depending on the host’s previous state of T-cell immunocompetency. The finding in germ-free mice also indicates that much of the homeostatic proliferation of naive T cells occurs in the absence of any foreign antigens.

Among the various subsets of T cells, memory CD4 cells are probably the least well understood in terms of their homeostatic requirements. Recent research indicates that survival of antigen-specific memory CD4 cells is supported by IL-7, whereas spontaneously generated polyclonal memory phenotype cells can also use signals from contact with self-MHC-peptide ligands. One potential problem with studying memory phenotype cells in normal mice is that these cells appear to be heterogeneous in terms of their homeostatic requirements. Thus, whereas antigen-specific memory CD4 cells are acutely dependent on IL-7 for survival, a population of polyclonal memory phenotype cells is independent of IL-7 (and IL-15) for survival and homeostatic proliferation.

The origin and the homeostatic requirements of these IL-7/IL-15–independent memory phenotype CD4 cells are unclear, but compared with antigen-specific memory CD4 cells, these cells appear to be at a higher state of activation, because they undergo a faster rate of homeostatic proliferation. The factors that support the generation and maintenance of various populations of memory phenotype T cells are currently unknown. Nonetheless, these cells may play a significant role in influencing the homeostatic behavior of other subsets of T cells through competition for homeostatic factors.

Publications

Baccala, R., Witherden, D., Gonzalez-Quintial, R., Dummer, W., Surh, C.D., Havran, W.L., Theofilopoulos, A.N. γδ T cell homeostasis is controlled by IL-7 and IL-15 together with subset-specific factors. J. Immunol. 174:4606, 2005.

Kieper, W.C., Troy, A., Burghardt, J.T., Ramsey, C., Lee, J.Y., Jiang, H.-Q., Dummer, W., Shen, H., Cebra, J.J., Surh, C.D. Recent immune status determines the source of antigens that drive homeostatic T cell expansion. J. Immunol. 174:3158, 2005.

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