Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a T cell surface protein that is homologous to CD28 and binds to the B7 family of ligands. Unlike CD28, CTLA-4 interaction transmits a negative signal in T cells, leading to suppression of proliferation. CTLA-4 is constitutively expressed on regulatory T cells (Tregs) but is also inducible in effector T cells. The mechanisms driving transcriptional regulation of CTLA-4 are poorly understood. Our previous work identified a bona fide NFAT1 binding site in the proximal promoter for effector T cells. In addition, we found histone acetylation occurred after stimulation.
As a result of its role in suppressing T cell proliferation, CTLA-4 is important for regulation of T cell responses. CTLA-4-immunoglobulin fusion proteins have shown efficacy to quell the overactive immune system in various types of autoimmune diseases. Alternatively, blocking antibodies to CTLA-4 have been used in cancer therapies to boost the anti-tumor immune response. Malignant cells of cutaneous T cell lymphoma (CTCL) express elevated levels of CTLA-4, which may contribute to reduced
tumor immunity as the disease progresses. The objective of this work was to identify mechanisms of transcriptional regulation of CTLA-4 to better understand how this gene can be modulated to potentially cater the immune response for a variety of immune-mediated diseases.
The major findings of this work include a mechanism by which proteasome inhibition augments CTLA-4 transcription in normal primary human CD4 T cells. The Th2 associated transcription factor GATA3 is both elevated and activated by phosphorylation after treatment with the proteasome inhibitor bortezomib, which in turn leads to CTLA-4 transcriptional activation in primary CD4 T cells. This finding may in part explain the increase in CTLA-4 found in CTCL, where GATA3 is also more abundant, particularly in its phosphorylated state. The increased CTLA-4 in our primary cell model is capable of suppressing T cell proliferation, demonstrating the potency of transcriptional modulation of this gene. Additionally we explored epigenetic and topological modifications that occur for CTLA-4 activation. We found the histone acetyltransferases p300 is responsible for histone 3 acetylation at the CTLA-4 promoter, and its activity is required for CTLA-4 transcription. We also discovered a previously undiscovered role for topoisomerase I in expression of a variety of induced genes, including CTLA-4. These results define novel mechanisms governing transcriptional activation of CTLA-4 in human effector CD4 T cells.
","abstract_html":"<p>Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a T cell surface protein that is homologous to CD28 and binds to the B7 family of ligands. Unlike CD28, CTLA-4 interaction transmits a negative signal in T cells, leading to suppression of proliferation. CTLA-4 is constitutively expressed on regulatory T cells (Tregs) but is also inducible in effector T cells. The mechanisms driving transcriptional regulation of CTLA-4 are poorly understood. Our previous work identified a bona fide NFAT1 binding site in the proximal promoter for effector T cells. In addition, we found histone acetylation occurred after stimulation.</p> <p>As a result of its role in suppressing T cell proliferation, CTLA-4 is important for regulation of T cell responses. CTLA-4-immunoglobulin fusion proteins have shown efficacy to quell the overactive immune system in various types of autoimmune diseases. Alternatively, blocking antibodies to CTLA-4 have been used in cancer therapies to boost the anti-tumor immune response. Malignant cells of cutaneous T cell lymphoma (CTCL) express elevated levels of CTLA-4, which may contribute to reduced</p> <p>tumor immunity as the disease progresses. The objective of this work was to identify mechanisms of transcriptional regulation of CTLA-4 to better understand how this gene can be modulated to potentially cater the immune response for a variety of immune-mediated diseases.</p> <p>The major findings of this work include a mechanism by which proteasome inhibition augments CTLA-4 transcription in normal primary human CD4 T cells. The Th2 associated transcription factor GATA3 is both elevated and activated by phosphorylation after treatment with the proteasome inhibitor bortezomib, which in turn leads to CTLA-4 transcriptional activation in primary CD4 T cells. This finding may in part explain the increase in CTLA-4 found in CTCL, where GATA3 is also more abundant, particularly in its phosphorylated state. The increased CTLA-4 in our primary cell model is capable of suppressing T cell proliferation, demonstrating the potency of transcriptional modulation of this gene. Additionally we explored epigenetic and topological modifications that occur for CTLA-4 activation. We found the histone acetyltransferases p300 is responsible for histone 3 acetylation at the CTLA-4 promoter, and its activity is required for CTLA-4 transcription. We also discovered a previously undiscovered role for topoisomerase I in expression of a variety of induced genes, including CTLA-4. These results define novel mechanisms governing transcriptional activation of CTLA-4 in human effector CD4 T cells.</p>","abstract_has_math":false,"creators":["Gibson, Heather"],"institution":null,"degree_name":"Ph.D.","degree_level":"Open Access Dissertation","degree_discipline":"Immunology and Microbiology","degree_department":null,"school":null,"contributors":["Henry K. Wong","Wei-Zen Wei"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2011,"date_issued":"2011-01-01T08:00:00Z","date_published":"2011-01-01T08:00:00Z","updated_at":"2026-07-24T05:58:49Z","subjects":["Immunology and Infectious Disease"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.wayne.edu/oa_dissertations/237","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Henry K. Wong","Wei-Zen Wei"]},{"key":"dc:creator","label":"Author","values":["Gibson, Heather"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2011-01-01T08:00:00Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Immunology and Microbiology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Open Access Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Immunology and Infectious Disease"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.wayne.edu/oa_dissertations/237"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a T cell surface protein that is homologous to CD28 and binds to the B7 family of ligands. Unlike CD28, CTLA-4 interaction transmits a negative signal in T cells, leading to suppression of proliferation. CTLA-4 is constitutively expressed on regulatory T cells (Tregs) but is also inducible in effector T cells. The mechanisms driving transcriptional regulation of CTLA-4 are poorly understood. Our previous work identified a bona fide NFAT1 binding site in the proximal promoter for effector T cells. In addition, we found histone acetylation occurred after stimulation.
As a result of its role in suppressing T cell proliferation, CTLA-4 is important for regulation of T cell responses. CTLA-4-immunoglobulin fusion proteins have shown efficacy to quell the overactive immune system in various types of autoimmune diseases. Alternatively, blocking antibodies to CTLA-4 have been used in cancer therapies to boost the anti-tumor immune response. Malignant cells of cutaneous T cell lymphoma (CTCL) express elevated levels of CTLA-4, which may contribute to reduced
tumor immunity as the disease progresses. The objective of this work was to identify mechanisms of transcriptional regulation of CTLA-4 to better understand how this gene can be modulated to potentially cater the immune response for a variety of immune-mediated diseases.
The major findings of this work include a mechanism by which proteasome inhibition augments CTLA-4 transcription in normal primary human CD4 T cells. The Th2 associated transcription factor GATA3 is both elevated and activated by phosphorylation after treatment with the proteasome inhibitor bortezomib, which in turn leads to CTLA-4 transcriptional activation in primary CD4 T cells. This finding may in part explain the increase in CTLA-4 found in CTCL, where GATA3 is also more abundant, particularly in its phosphorylated state. The increased CTLA-4 in our primary cell model is capable of suppressing T cell proliferation, demonstrating the potency of transcriptional modulation of this gene. Additionally we explored epigenetic and topological modifications that occur for CTLA-4 activation. We found the histone acetyltransferases p300 is responsible for histone 3 acetylation at the CTLA-4 promoter, and its activity is required for CTLA-4 transcription. We also discovered a previously undiscovered role for topoisomerase I in expression of a variety of induced genes, including CTLA-4. These results define novel mechanisms governing transcriptional activation of CTLA-4 in human effector CD4 T cells.
"]},{"key":"dc:title","label":"Title","values":["Ctla-4 transcriptional activation: regulation of induced expression"]}]}],"canonical_facts":{"dc:contributor":["Henry K. Wong","Wei-Zen Wei"],"dc:creator":["Gibson, Heather"],"dc:date.available":["2011-01-01T08:00:00Z"],"dc:description.abstract":["Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a T cell surface protein that is homologous to CD28 and binds to the B7 family of ligands. Unlike CD28, CTLA-4 interaction transmits a negative signal in T cells, leading to suppression of proliferation. CTLA-4 is constitutively expressed on regulatory T cells (Tregs) but is also inducible in effector T cells. The mechanisms driving transcriptional regulation of CTLA-4 are poorly understood. Our previous work identified a bona fide NFAT1 binding site in the proximal promoter for effector T cells. In addition, we found histone acetylation occurred after stimulation.
As a result of its role in suppressing T cell proliferation, CTLA-4 is important for regulation of T cell responses. CTLA-4-immunoglobulin fusion proteins have shown efficacy to quell the overactive immune system in various types of autoimmune diseases. Alternatively, blocking antibodies to CTLA-4 have been used in cancer therapies to boost the anti-tumor immune response. Malignant cells of cutaneous T cell lymphoma (CTCL) express elevated levels of CTLA-4, which may contribute to reduced
tumor immunity as the disease progresses. The objective of this work was to identify mechanisms of transcriptional regulation of CTLA-4 to better understand how this gene can be modulated to potentially cater the immune response for a variety of immune-mediated diseases.
The major findings of this work include a mechanism by which proteasome inhibition augments CTLA-4 transcription in normal primary human CD4 T cells. The Th2 associated transcription factor GATA3 is both elevated and activated by phosphorylation after treatment with the proteasome inhibitor bortezomib, which in turn leads to CTLA-4 transcriptional activation in primary CD4 T cells. This finding may in part explain the increase in CTLA-4 found in CTCL, where GATA3 is also more abundant, particularly in its phosphorylated state. The increased CTLA-4 in our primary cell model is capable of suppressing T cell proliferation, demonstrating the potency of transcriptional modulation of this gene. Additionally we explored epigenetic and topological modifications that occur for CTLA-4 activation. We found the histone acetyltransferases p300 is responsible for histone 3 acetylation at the CTLA-4 promoter, and its activity is required for CTLA-4 transcription. We also discovered a previously undiscovered role for topoisomerase I in expression of a variety of induced genes, including CTLA-4. These results define novel mechanisms governing transcriptional activation of CTLA-4 in human effector CD4 T cells.
"],"dc:identifier":["https://digitalcommons.wayne.edu/oa_dissertations/237"],"dc:subject":["Immunology and Infectious Disease"],"dc:title":["Ctla-4 transcriptional activation: regulation of induced expression"],"thesis:degree_discipline":["Immunology and Microbiology"],"thesis:degree_level":["Open Access Dissertation"],"thesis:degree_name":["Ph.D."]},"updated_at":"2026-07-24T05:58:49Z"}