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Cytokine- and Transcription Factor-Mediated Mechanisms of T Follicular Helper Cell Regulation.

紀錄類型:	書目-語言資料,手稿 : Monograph/item
正題名/作者:	Cytokine- and Transcription Factor-Mediated Mechanisms of T Follicular Helper Cell Regulation./
作者:	Read, Kaitlin Adele.
面頁冊數:	1 online resource (336 pages)
附註:	Source: Dissertations Abstracts International, Volume: 85-03, Section: B.
Contained By:	Dissertations Abstracts International85-03B.
標題:	Cellular biology. -
電子資源:	click for full text (PQDT)
ISBN:	9798380370202

Cytokine- and Transcription Factor-Mediated Mechanisms of T Follicular Helper Cell Regulation.
Read, Kaitlin Adele.

Cytokine- and Transcription Factor-Mediated Mechanisms of T Follicular Helper Cell Regulation. - 1 online resource (336 pages)

Source: Dissertations Abstracts International, Volume: 85-03, Section: B.

Thesis (Ph.D.)--The Ohio State University, 2023.

Includes bibliographical references

CD4+ T "helper" populations comprise a key subset of adaptive immune cells that are critical for orchestrating antigen-specific immune responses for both the clearance of pathogens and elimination of cancers. This population responds to insult-specific environmental signals, including those from cytokines, by differentiating into a number of functionally distinct subsets, which produce cytokines and interact with additional immune cells to effect their diverse functions. Of these, T follicular helper (TFH) cells are established coordinators of humoral immune responses, as they engage in bi-directional signaling with B cells, via both cell surface receptors and cytokine signals. Ultimately, this interaction is critical for the germinal center reaction, during which B cells are activated, proliferate, and are ultimately selected to support the generation of high-affinity B cell clones, and thus, high-affinity antibodies. This process is also required for the formation of long-lived plasma cell populations, which are a key part of both natural and vaccine-induced immunological memory. In contrast to this important role, TFH cells have also been implicated in autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus, and others, for which the production of autoantibodies is a key aspect of pathogenesis. To date, the full scope of mechanisms underlying TFH cell differentiation are incompletely understood. Complicating this process, TFH cells are not comprised of a single, monolithic population, and numerous studies support the existence and function of 'polyfunctional' TFH populations which exhibit characteristics of other CD4+ T cell subsets (recently reviewed in (1)). Thus, it will be important for TFH-focused work to identify not only shared, but also TFH-subset-specific, regulatory mechanisms. Here, I present findings regarding both cytokine- and transcription-mediated factor mechanisms by which TFH populations are regulated.First, we identify the contribution of cytokine signals to the differentiation of T helper 1 (TH1)-biased TFH (TFH1) cells, which exhibit characteristics of TH1 cells, including the production of IFN-γ, and have recognized roles in both immune responses to pathogens and the pathogenesis of autoimmune disease. Given their apparent importance to human health, there is interest in understanding the mechanisms that regulate TFH1 cell formation and function. However, their origin and the molecular requirements for their differentiation are unclear. Here, we describe a population of murine TH1-derived, TFH1-like cells that express the chemokine receptor Cxcr3 and produce both the TH1 cytokine interferon-? and the TFH-associated cytokine interleukin-21 (IL-21). These TFH1-like cells promote B cell activation and antibody production at levels indistinguishable from conventional IL-6-derived TFH-like cells. Regarding their regulatory requirements, we find that IL-12 signaling is necessary for the differentiation and function of this TFH1-like cell population. Specifically, IL-12-dependent activation of STAT4, and unexpectedly STAT3, promotes increased expression of IL-21 and the TFH lineage-defining transcription factor Bcl-6 in TFH1-like cells. Taken together, these findings provide insight into the potential origin and differentiation requirements of TFH1 cells.Second, we identify Aiolos as a reciprocal regulator of TFH and cytotoxic programming. Effective immunity against intracellular pathogens such as influenza and SARS-CoV-2 requires the generation of CD4+ T cell subsets that coordinate diverse aspects of the immune response, including TFH and TH1 cells. A third population, CD4+ cytotoxic T lymphocytes (CD4-CTLs), facilitates clearance of infection via mechanisms normally associated with CD8+ T cells. The mechanisms that guide the differentiation of these complementary cell populations are incompletely understood. Here, we identify the transcription factor Aiolos as a reciprocal regulator of TFH and CD4-CTL programming. We demonstrate that Aiolos-deficient cells exhibit increased production of cytotoxic effector molecules during influenza infection, including perforin and granzyme B. We further find that loss of Aiolos results in global disruptions to the TFH transcriptome. This includes reduced expression of key TFH-associated transcription factors, such as Bcl-6 and Zfp831, which we identify as direct Aiolos targets. We further demonstrate that Aiolos deficiency allows for elevated expression of IL-2R subunits, enhanced sensitivity to IL-2, and increased STAT5 association with key CD4-CTL gene targets. These include CTL-associated transcription factors (Eomes, Blimp-1), effector molecules (granzyme B, perforin, IFN-γ), and IL2Rα itself. Thus, our collective findings identify Aiolos as a pivotal regulator of CD4-CTL and TFH programming and highlight its potential as a target for manipulating CD4+ T cell cytotoxic and humoral responses.Together, the work presented in this dissertation provides novel i) insights into TFH cell biology, and ii) potential targets for the generation of immunotherapies to support vaccine efficacy and the treatment of human disease.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798380370202Subjects--Topical Terms:

1148666
Cellular biology.
Subjects--Index Terms:

T cell biologyIndex Terms--Genre/Form:

554714
Electronic books.

Cytokine- and Transcription Factor-Mediated Mechanisms of T Follicular Helper Cell Regulation.
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This process is also required for the formation of long-lived plasma cell populations, which are a key part of both natural and vaccine-induced immunological memory. In contrast to this important role, TFH cells have also been implicated in autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus, and others, for which the production of autoantibodies is a key aspect of pathogenesis. To date, the full scope of mechanisms underlying TFH cell differentiation are incompletely understood. Complicating this process, TFH cells are not comprised of a single, monolithic population, and numerous studies support the existence and function of 'polyfunctional' TFH populations which exhibit characteristics of other CD4+ T cell subsets (recently reviewed in (1)). Thus, it will be important for TFH-focused work to identify not only shared, but also TFH-subset-specific, regulatory mechanisms. Here, I present findings regarding both cytokine- and transcription-mediated factor mechanisms by which TFH populations are regulated.First, we identify the contribution of cytokine signals to the differentiation of T helper 1 (TH1)-biased TFH (TFH1) cells, which exhibit characteristics of TH1 cells, including the production of IFN-γ, and have recognized roles in both immune responses to pathogens and the pathogenesis of autoimmune disease. Given their apparent importance to human health, there is interest in understanding the mechanisms that regulate TFH1 cell formation and function. However, their origin and the molecular requirements for their differentiation are unclear. Here, we describe a population of murine TH1-derived, TFH1-like cells that express the chemokine receptor Cxcr3 and produce both the TH1 cytokine interferon-? and the TFH-associated cytokine interleukin-21 (IL-21). These TFH1-like cells promote B cell activation and antibody production at levels indistinguishable from conventional IL-6-derived TFH-like cells. Regarding their regulatory requirements, we find that IL-12 signaling is necessary for the differentiation and function of this TFH1-like cell population. Specifically, IL-12-dependent activation of STAT4, and unexpectedly STAT3, promotes increased expression of IL-21 and the TFH lineage-defining transcription factor Bcl-6 in TFH1-like cells. Taken together, these findings provide insight into the potential origin and differentiation requirements of TFH1 cells.Second, we identify Aiolos as a reciprocal regulator of TFH and cytotoxic programming. Effective immunity against intracellular pathogens such as influenza and SARS-CoV-2 requires the generation of CD4+ T cell subsets that coordinate diverse aspects of the immune response, including TFH and TH1 cells. A third population, CD4+ cytotoxic T lymphocytes (CD4-CTLs), facilitates clearance of infection via mechanisms normally associated with CD8+ T cells. The mechanisms that guide the differentiation of these complementary cell populations are incompletely understood. Here, we identify the transcription factor Aiolos as a reciprocal regulator of TFH and CD4-CTL programming. We demonstrate that Aiolos-deficient cells exhibit increased production of cytotoxic effector molecules during influenza infection, including perforin and granzyme B. We further find that loss of Aiolos results in global disruptions to the TFH transcriptome. This includes reduced expression of key TFH-associated transcription factors, such as Bcl-6 and Zfp831, which we identify as direct Aiolos targets. We further demonstrate that Aiolos deficiency allows for elevated expression of IL-2R subunits, enhanced sensitivity to IL-2, and increased STAT5 association with key CD4-CTL gene targets. These include CTL-associated transcription factors (Eomes, Blimp-1), effector molecules (granzyme B, perforin, IFN-γ), and IL2Rα itself. Thus, our collective findings identify Aiolos as a pivotal regulator of CD4-CTL and TFH programming and highlight its potential as a target for manipulating CD4+ T cell cytotoxic and humoral responses.Together, the work presented in this dissertation provides novel i) insights into TFH cell biology, and ii) potential targets for the generation of immunotherapies to support vaccine efficacy and the treatment of human disease.
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