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theses

The BTB-ZF transcriptional regulator, promyelocytic leukemia zinc finger (PLZF), is known to control the innate phenotype and effector functions of NKT cells and γδ T cells. The unstudied protein, Btbd11, has been shown to be transcriptionally controlled by PLZF and directly interact with PLZF via the shared BTB protein-interaction domain. In order to determine if Btbd11 plays a role in modulating the function of PLZF, we have generated a mouse exhibiting induced overexpression of Btbd11 in all T cells. In conjunction with existing mice ectopically expressing PLZF in all T cells, we investigated the impact that these factors had upon the phenotype and function of T cells. Concurrently, we utilized another mouse line with reduced Btbd11 expression (Btbd11 GT mice) to determine the role that Btbd11 alone plays in controlling various characteristics of T cell populations. Significantly, mice with overexpression of both Btbd11 and PLZF (dTG mice) exhibited ~11% of CD8+ T cells capable of producing IL-17a upon in vitro activation. This population of IL-17a producing CD8+ T cells is almost non-existent in wild type mice and represents a significant proinflammatory phenotype. Total liver γδ T cell populations were also found to be dependent on levels of Btbd11, as dTG mice had a two-fold expansion while Btbd11 GT mice showed a three-fold contraction of γδ T cells compared to wild type. In vivo studies of Concanavalin A induced liver damage determined that Btbd11 GT mice exhibited a four-fold reduction versus wild type in serum ALT activity, an enzyme released via liver damage. Overexpression of Btbd11 and PLZF results in the expansion of proinflammatory effector cells while reduced expression of Btbd11 results in a protection from innate T cell-mediated liver damage, indicating the correlation between Btbd11 and the characteristic proinflammatory phenotype seen in these innate T cell subsets. We conclude that Btbd11 and PLZF interact differently with each other and other co-factors depending upon their setting within different immune cells. These studies indicate a potential role for Btbd11 in modifying the phenotype and effector function of various T cell subsets by regulating PLZF’s ability to exert transcriptional control.

ETD_6725

M.S.

Includes bibliographical references

by Andrew R. Chavkin

doi:10.7282/T38W3G82

ETD graduate

The author owns the copyright to this work.