Untangling the Adjuvanticity of mRNA Vaccines: Nucleoside-Modified mRNA and Lipid Nanoparticles Cooperate to Drive T Follicular Helper Cell Responses
Untangling the Adjuvanticity of mRNA Vaccines: Nucleoside-Modified mRNA and Lipid Nanoparticles Cooperate to Drive T Follicular Helper Cell Responses
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211152001
- ISBN
- 9798384024422
- DDC
- 616.079
- 서명/저자
- Untangling the Adjuvanticity of mRNA Vaccines: Nucleoside-Modified mRNA and Lipid Nanoparticles Cooperate to Drive T Follicular Helper Cell Responses
- 발행사항
- [Sl] : University of Pennsylvania, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 179 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-02, Section: B.
- 주기사항
- Advisor: Locci, Michela;Laufer, Terri.
- 학위논문주기
- Thesis (Ph.D.)--University of Pennsylvania, 2024.
- 초록/해제
- 요약Vaccines provide protection from pathogens by eliciting high affinity, neutralizing antibody responses through germinal center (GC) reactions. Within GCs, T follicular helper (Tfh) cells orchestrate the selection of affinity-matured memory B cells and long-lived plasma cells. With the emergence of the COVID-19 pandemic, the utility of the messenger RNA (mRNA) vaccine platform has become increasingly evident due to its ease of adaptability to target emerging viral variants as well as its ability to drive potent humoral responses. Data from our group has shown that these potent humoral immune responses correlate with a robust induction of Tfh cells, however, the mechanism of Tfh induction by mRNA vaccines is largely unknown. Most mRNA vaccines consist of nucleoside-modified mRNA encoding the antigen-of-interest encapsulated in lipid nanoparticles (LNPs), which protect the mRNA from degradation and allow for its delivery into the cytosol. Herein, we have uncoupled distinct, yet complimentary, roles for both the LNP and nucleoside-modified mRNA in promoting Tfh cell responses. We demonstrated that LNPs are robust Tfh cell inducing adjuvants when combined with protein antigens in the absence of mRNA through a mechanism that is heavily reliant on the local production of IL-6 within the draining lymph nodes (dLNs). Through a proximity dependent labeling (LIPSTIC) approach coupled with single-cell transcriptomic analysis, we additionally discovered that LNPs drive broad activating effects on type-2 conventional dendritic cells (cDC2s) within the dLN irrespective of T cell help, which included the upregulation of a "pro-Tfh cell" program. Interestingly, when we interrogated the quality of the immune response driven by both LNPs and nucleoside-modified mRNAs, we found that LNPs favored a Th2- biased Tfh cell response while nucleoside-modified mRNAs drove a Th1-biased response. Upon further interrogation, we discovered that this Th1-bias driven by nucleoside-modified mRNA was dependent on type I interferons which acted directly on DCs to drive their maturation and increase the magnitude of GC responses. Taken together, we believe that the information gleaned from these studies will begin to unravel the mechanism by which mRNA vaccines induce Tfh cells, providing critical information for the rational design of vaccines against hard-to-neutralize pathogens.
- 일반주제명
- Immunology
- 일반주제명
- Nanotechnology
- 일반주제명
- Molecular biology
- 키워드
- mRNA vaccines
- 키워드
- Messenger RNA
- 기타저자
- University of Pennsylvania Immunology
- 기본자료저록
- Dissertations Abstracts International. 86-02B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a616.079
■1001 ▼aBettini, Emily Ann.
■24510▼aUntangling the Adjuvanticity of mRNA Vaccines: Nucleoside-Modified mRNA and Lipid Nanoparticles Cooperate to Drive T Follicular Helper Cell Responses
■260 ▼a[Sl]▼bUniversity of Pennsylvania▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a179 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-02, Section: B.
■500 ▼aAdvisor: Locci, Michela;Laufer, Terri.
■5021 ▼aThesis (Ph.D.)--University of Pennsylvania, 2024.
■520 ▼aVaccines provide protection from pathogens by eliciting high affinity, neutralizing antibody responses through germinal center (GC) reactions. Within GCs, T follicular helper (Tfh) cells orchestrate the selection of affinity-matured memory B cells and long-lived plasma cells. With the emergence of the COVID-19 pandemic, the utility of the messenger RNA (mRNA) vaccine platform has become increasingly evident due to its ease of adaptability to target emerging viral variants as well as its ability to drive potent humoral responses. Data from our group has shown that these potent humoral immune responses correlate with a robust induction of Tfh cells, however, the mechanism of Tfh induction by mRNA vaccines is largely unknown. Most mRNA vaccines consist of nucleoside-modified mRNA encoding the antigen-of-interest encapsulated in lipid nanoparticles (LNPs), which protect the mRNA from degradation and allow for its delivery into the cytosol. Herein, we have uncoupled distinct, yet complimentary, roles for both the LNP and nucleoside-modified mRNA in promoting Tfh cell responses. We demonstrated that LNPs are robust Tfh cell inducing adjuvants when combined with protein antigens in the absence of mRNA through a mechanism that is heavily reliant on the local production of IL-6 within the draining lymph nodes (dLNs). Through a proximity dependent labeling (LIPSTIC) approach coupled with single-cell transcriptomic analysis, we additionally discovered that LNPs drive broad activating effects on type-2 conventional dendritic cells (cDC2s) within the dLN irrespective of T cell help, which included the upregulation of a "pro-Tfh cell" program. Interestingly, when we interrogated the quality of the immune response driven by both LNPs and nucleoside-modified mRNAs, we found that LNPs favored a Th2- biased Tfh cell response while nucleoside-modified mRNAs drove a Th1-biased response. Upon further interrogation, we discovered that this Th1-bias driven by nucleoside-modified mRNA was dependent on type I interferons which acted directly on DCs to drive their maturation and increase the magnitude of GC responses. Taken together, we believe that the information gleaned from these studies will begin to unravel the mechanism by which mRNA vaccines induce Tfh cells, providing critical information for the rational design of vaccines against hard-to-neutralize pathogens.
■590 ▼aSchool code: 0175.
■650 4▼aImmunology
■650 4▼aNanotechnology
■650 4▼aMolecular biology
■653 ▼amRNA vaccines
■653 ▼aLipid nanoparticles
■653 ▼aMessenger RNA
■653 ▼aT follicular helper cells
■690 ▼a0982
■690 ▼a0652
■690 ▼a0307
■71020▼aUniversity of Pennsylvania▼bImmunology.
■7730 ▼tDissertations Abstracts International▼g86-02B.
■790 ▼a0175
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17162338▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
