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Welcome to the Surh Laboratory

Research - Regulation of Mature T Cell Homeostasis

Charles D. Surh
Chris Ramsey
Jared F. Purton
Ester. M.M. van Leeuwen
Joon Youb Lee
David M. Kim
Onur Boyman*
Joyce T. Tan** 
Curie Ahn***

* Current address: Ludwig Institute for Cancer Research, University of Lausanne, Switzerland
**Current address: Anadys Pharmaceutical. La Jolla, CA, USA
***Current address: Seoul National University Hospital, Seoul, Korea

The homeostasis of mature T cells is largely governed by two related cytokines, IL-7 and IL-15, which bind to the receptors belonging to the common gamma chain (CD132) receptor family. Other members of the CD132 family include receptors for IL-2, IL-4, IL-9 and IL-21. In conjunction with signals from contact with self-peptide/MHC ligands, IL-7 controls survival of naïve T cells. Memory T cells, which are at a higher state of activation than naïve T cells, depend on both IL-7 and IL-15 for survival and to undergo intermittent cell division. Memory CD4+ T cells are generally more dependent on IL-7 than IL-15 for their homeostasis, whereas memory CD8+ T cells rely primarily on IL-7 for survival and IL-15 for periodic cell division. Indicative of their cytokine requirements, the dimeric receptor for IL-7 (CD127/CD132) is expressed at high levels on naïve and memory T cells, whereas the dimeric receptor for IL-15 (CD122/CD132) is negligible on naïve T cells, slightly on memory CD4+ T cells, and highly expressed on memory CD8+ T cells. Both IL-7 and IL-15 are not produced by T cells, but by epithelial, stromal and antigen-presenting cells.

IL-2, which is produced by T cells for autocrine purposes, is closely related to IL-15. Recognition of IL-2 by T cells is mediated by the high affinity trimeric receptor for IL-2 (CD25/CD122/CD132), two chains which are shared by the IL-15 receptor. Indeed the IL-15 receptor can also recognize IL-2 at a lower affinity. Interestingly, injecting a monoclonal antibody (mAb) to IL-2, which is believed to deplete the cytokine, increases the background turnover rate of memory CD8+ T cells. This finding was interpreted to indicate that IL-2, unlike IL-15, dampens the homeostasis of memory CD8+ cells. Recent work, however, indicates that this interpretation is untrue. This is because the anti-IL-2 mAb, instead of depleting IL-2, actually boosts the biological activity of IL-2. Hence, the ability of anti-IL-2 mAb to elevate turnover of memory CD8+ T cells did not occur in the absence of IL-2, and more importantly, injecting anti-IL-2 mAb pre-complexed with IL-2 dramatically induced memory CD8+ T cells to undergo prodigious rapid proliferation. Indeed, administration of anti-IL-2 mAb + IL-2 complex was found to induce 100-200-fold greater expansion of memory CD8+ T cells than injecting IL-2 alone. The IL-2/mAb complex stimulated CD8+ T cells through the dimeric IL-15 receptor rather than the trimeric IL-2 receptor as its stimulatory activity was also evident on CD25- CD8+ T cells.

Exactly how the bound mAb enhances the activity of IL-2 is unknown. Nonetheless, it is clear that mAbs augment the cytokine activity in vivo, but not under in vitro conditions, and the Fc portion of the mAb is required for its intensifying role. These findings suggest that mAb boosts the cytokine activity by concentrating the cytokine onto the cell surface of antigen-presenting cells and/or by prolonging the half-life of the cytokine. The specificity of the mAb also determines its ability to enhance the activity of IL-2 to its particular receptors. Thus, one particular anti-IL-2 mAb had the capacity to stimulate T cells expressing the trimeric IL-2 receptor, such as regulatory T cells, but not memory CD8+ T cells that express the dimeric IL-15/IL-2 receptor. The ability of mAb to boost the activity of the bound cytokine appears to be generally applicable as the biological activity of other cytokines, such as IL-4 and IL-7, can also be enhanced by binding to specific mAbs. The ability to induce expansion and activation of specific subsets of T cells by administration of cytokine/mAb complexes may offer a new way to modulate the immune response for therapeutic purposes: the immune response can be boosted against tumors and infectious agents by activating naïve and memory T cells, and alternatively, by inducing expansion of regulatory T cells, the immune responses against self, allergens and tissue grafts can be suppressed.