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Regulation of CD8+ T Cell Differentiation by Cytokines and T-box Transcription Factors
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Regulation of CD8+ T Cell Differentiation by Cytokines and T-box Transcription Factors. |
| 개인저자 | Reiser, John W. |
| 단체저자명 | University of Maryland, Baltimore. Molecular Medicine. |
| 발행사항 | [S.l.]: University of Maryland, Baltimore., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 145 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-03B. Dissertation Abstract International |
| ISBN | 9781085599115 |
| 학위논문주기 | Thesis (Ph.D.)--University of Maryland, Baltimore, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-03, Section: B.
Advisor: Singh, Nevil. |
| 이용제한사항 | This item must not be sold to any third party vendors. |
| 요약 | A protective immune response requires naive CD8+ T cells to differentiate into effector cells, some of which persist as a memory population to protect against future threats. This differentiation program is controlled by a transcriptional network involving the T-box transcription factors T-bet and Eomesodermin (Eomes). These factors are in turn differentially regulated by cytokines in the local milieu. The precise architecture of this regulatory network in terms of the individual, synergistic and redundant roles of T-bet, Eomes and critical cytokines is still poorly understood.Here we sought to clarify these regulatory pathways, using mice deficient in T-bet, Eomes or both. Our studies identify a key role for Eomes, but not T-bet, in regulating IL-10 expression by CD8+ T cells early after activation. We further reveal a feedback loop where Eomes and IL-10 cooperatively enhance the expression of the lymph-node homing selectin CD62L. Consistent with the importance of CD62L in promoting memory T cell homing to secondary lymphoid organs (SLOs), we identify a role for CD8+ T cell-intrinsic IL-10 in promoting the long-term persistence of memory cells in vivo. In contrast, T cells that home away from the SLOs become terminal effector T cells. Using tumor and infectious disease models, we report that these cells experience a second wave of T-bet induction in the tissue, which may contribute to a heightened effector response.We also define distinct roles for T-bet and Eomes in regulating effector and memory genes, highlighting their redundant role in repressing Tc2 and Tc17 differentiation in CD8+ T cells. Finally, we demonstrate that in the context of a tumor-specific immune response, the absence of both T-box transcription factors severely limits tumor infiltration without significant alteration in early proliferation or effector functions. Taken together, these findings offer new insights into how T-bet, Eomes and IL-10 regulate effector and memory responses in distinct tissues during the immune response. Future developments targeting individual aspects of T-box and cytokine signaling in T cells may help engineer precise outcomes in the context of tumor immunotherapies, vaccination and transplantation. |
| 일반주제명 | Immunology. Physiology. Public health. Health sciences. |
| 언어 | 영어 |
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: 이 자료의 원문은 한국교육학술정보원에서 제공합니다. |
