GENE REGULATORY EVENTS IN ESTABLISHING MATURE T CELL TOL

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Abstract

One of the fundamental questions of modern immunology is the control of CD4+ helper T-cell differentiation into subsets with discrete effector functions. Of particular interest is the regulation and functions of a unique class of CD4+,CD25+ T cells that express high levels of the winged fork head transcription factor, FoxP3. This subsets strictly controls the expression of [unreadable] cytokines and is in capable of producing growth cytokine such as IL-2 and IL-4. These cells have been shown to impair the activation of other conventional CD4+ T cells which could be important during autoimmune reactions; hence these cells are called "T regulatory" (Treg) cells. Despite a great deal of investigation, it is still unclear how the cells are capable of suppressing conventional T cells and what role they play in normal immune reactions. [unreadable] [unreadable] In order to examine the molecular basis of the suppressive effects of Tregs, we set up a co-cultivation system in which Tregs were used to suppress conventional CD4 T cells responding to T cell receptor agonists. We found that potent suppression could be observed with 1:1 mix of cells. Under these conditions, we observed that the conventional T cells underwent apoptosis. Furthermore, we found that the prevailing model of suppression of IL-2 gene transcription was incorrect. Death of the responding cells could quantitatively account for the loss of T cell response. We found that various common gamma chain cytokines were able to completely reverse the death due to Treg suppression. This appeared to be due to the fact that Tregs consumed, but could not produce, the cytokines and thereby deprived the conventional T cells of cytokines. In conjunction with these observations, we found that a deficiency of the Bim gene completely rescued T cells from Treg suppression. Taken together these data suggest that Treg cells cause an alternative form of severe deletion rather than suppression of cytokine transcription in the responding conventional T cells. Our observations shed new light on this unique population of T cells and may have importance for autoimmune disorders, infectious diseases, and tumor immunity.