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Epidermal Resident Memory T Cell Fitness Requires Antigen Encounter in the Skin
Epidermal Resident Memory T Cell Fitness Requires Antigen Encounter in the Skin
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202103704
- ISBN
- 9798293880485
- DDC
- 616.079
- 서명/저자
- Epidermal Resident Memory T Cell Fitness Requires Antigen Encounter in the Skin
- 발행사항
- [Sl] : University of Pittsburgh, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 139 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 87-03, Section: B.
- 주기사항
- Advisor: Kaplan, Daniel H.;Kane, Lawrence P.
- 학위논문주기
- Thesis (Ph.D.)--University of Pittsburgh, 2025.
- 초록/해제
- 요약When CD8+ effectors enter the skin, some persist long term where they can provide defense against subsequent challenges. These permanent residents in the periphery are called tissue resident memory T cells (TRM). Their persistence in the epidermis requires autocrine TGFs which is transactivated by integrins ⍺vβ6 and ⍺vβ8 expressed on keratinocytes. Precursors to TRM that encounter local cognate antigen in the epidermis during development outcompete bystander TRM that never encountered local antigen for activated TGFs, which results in enhanced persistence when levels of activated TGFs are limiting. However, the mechanism with which prior antigen encounter determines TRM persistence is still unknown. Further, the effects of prior local antigen encounter on TRM differentiation and function remain unexplored. Using acute inflammatory models, tumor models, as well as transcriptional analysis, I explored the role of prior local antigen encounter on TRM differentiation and function.In this thesis, I used single-cell RNA-seq analysis of endogenous epidermal TRM to reveal that local antigen experience in the epidermis resulted in an enhanced TRM differentiation signature compared to bystanders. During a recall response, I identified that local antigen-experienced TRM displayed faster kinetics of proliferation directly dependent on the TCR signal-strength of their initial peripheral antigen encounter. I also identified that local antigen-experienced TRM differentially expressed TGFsRIII, which increases the avidity of the TGFβRI/II receptor complex for TGFβ. Targeted ablation of Tgfbr3 impeded the ability of local antigen-experienced TRM to persist in the epidermis when activated TGFs was limiting, rendering these cells functionally identical to bystander TRM. However, I also discovered that despite the importance of antigen encounter for competition for TGFs, loss of competition for activated TGFs did not appear to functionally alter T cell function or specificity within a tumor. Thus, the work presented in this thesis demonstrates that antigen-driven TCR signaling in the epidermis during initial TRM differentiation results in a lower requirement for TGFs to persist in the skin, and an increased proliferative capacity during a recall response. Together, these data demonstrate that early local antigen encounter induces enhanced epidermal TRM fitness.
- 일반주제명
- Immunology
- 일반주제명
- Dermatology
- 일반주제명
- Microbiology
- 키워드
- Memory
- 키워드
- T cells
- 키워드
- CD8+ effectors
- 키워드
- Keratinocytes
- 기타저자
- University of Pittsburgh Microbiology and Immunology
- 기본자료저록
- Dissertations Abstracts International. 87-03B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a616.079
■1001 ▼aWeiss, Eric Smith.▼0(orcid)0000-0003-2352-0036
■24510▼aEpidermal Resident Memory T Cell Fitness Requires Antigen Encounter in the Skin
■260 ▼a[Sl]▼bUniversity of Pittsburgh▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a139 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 87-03, Section: B.
■500 ▼aAdvisor: Kaplan, Daniel H.;Kane, Lawrence P.
■5021 ▼aThesis (Ph.D.)--University of Pittsburgh, 2025.
■520 ▼aWhen CD8+ effectors enter the skin, some persist long term where they can provide defense against subsequent challenges. These permanent residents in the periphery are called tissue resident memory T cells (TRM). Their persistence in the epidermis requires autocrine TGFs which is transactivated by integrins ⍺vβ6 and ⍺vβ8 expressed on keratinocytes. Precursors to TRM that encounter local cognate antigen in the epidermis during development outcompete bystander TRM that never encountered local antigen for activated TGFs, which results in enhanced persistence when levels of activated TGFs are limiting. However, the mechanism with which prior antigen encounter determines TRM persistence is still unknown. Further, the effects of prior local antigen encounter on TRM differentiation and function remain unexplored. Using acute inflammatory models, tumor models, as well as transcriptional analysis, I explored the role of prior local antigen encounter on TRM differentiation and function.In this thesis, I used single-cell RNA-seq analysis of endogenous epidermal TRM to reveal that local antigen experience in the epidermis resulted in an enhanced TRM differentiation signature compared to bystanders. During a recall response, I identified that local antigen-experienced TRM displayed faster kinetics of proliferation directly dependent on the TCR signal-strength of their initial peripheral antigen encounter. I also identified that local antigen-experienced TRM differentially expressed TGFsRIII, which increases the avidity of the TGFβRI/II receptor complex for TGFβ. Targeted ablation of Tgfbr3 impeded the ability of local antigen-experienced TRM to persist in the epidermis when activated TGFs was limiting, rendering these cells functionally identical to bystander TRM. However, I also discovered that despite the importance of antigen encounter for competition for TGFs, loss of competition for activated TGFs did not appear to functionally alter T cell function or specificity within a tumor. Thus, the work presented in this thesis demonstrates that antigen-driven TCR signaling in the epidermis during initial TRM differentiation results in a lower requirement for TGFs to persist in the skin, and an increased proliferative capacity during a recall response. Together, these data demonstrate that early local antigen encounter induces enhanced epidermal TRM fitness.
■590 ▼aSchool code: 0178.
■650 4▼aImmunology
■650 4▼aDermatology
■650 4▼aMicrobiology
■653 ▼aMemory
■653 ▼aT cells
■653 ▼aTissue resident memory
■653 ▼aCD8+ effectors
■653 ▼aKeratinocytes
■690 ▼a0982
■690 ▼a0410
■690 ▼a0757
■71020▼aUniversity of Pittsburgh▼bMicrobiology and Immunology.
■7730 ▼tDissertations Abstracts International▼g87-03B.
■790 ▼a0178
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17358240▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
