Differential IL-2 Expression by Effector CD8 T cells and Fate Determination

效应 CD8 T 细胞的差异 IL-2 表达和命运决定

基本信息

  • 批准号:
    10047445
  • 负责人:
  • 金额:
    $ 23.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-14 至 2022-08-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT A signature of polyfunctional, long-lived memory CD8 T cells, IL-2 production capability is believed to be largely downregulated in effector CD8 T cells. Using novel phenotypic markers that distinguish effector cytotoxic T lymphocytes (CTLs) into memory-fated (memory precursor effector cell, MPEC) and terminally differentiated (short-lived effector cell, SLEC) subsets, our studies were the first to establish that memory CD8 T cells retain the ability to produce copious amounts of IL-2 throughout differentiation; even during the effector phase. We found that MPECs are capable of robust IL-2 production alongside vigorous production of effector molecules (granzyme B, IFN-γ and TNF-α). This was surprising since naïve CD8 T cells are believed to largely lose IL-2 production capability after activation and effector differentiation. Using murine models of conditional il2 ablation in a subset of antigen-specific CD8 T cells, we have further discovered that autocrine IL-2 is functionally relevant, and is needed during primary responses (and not during secondary responses) to imprint the hallmark memory property of potent recall expansion and protection against secondary challenge. Intriguingly, IL-2-sufficient MPECs transduce paracrine IL-2 signals less efficiently than their IL-2 non- producing SLEC counterparts. SLECs do not make IL-2, but receive strong paracrine IL-2 signals through increased expression of the high affinity IL-2R, and expand to ~10-fold higher numbers than MPECs. We hypothesize that autocrine IL-2 signaling in MPECs versus strong paracrine IL-2 signals in SLECs institute qualitatively distinct gene expression programs, thus resulting in their starkly disparate life versus death fates. Alternatively, it is possible that despite retaining the ability for IL-2 production, MPECs in actuality do not produce IL-2 in vivo, thus undergoing lesser expansion and preserving their memory fitness for recall expansion. Much of our understanding of the role of IL-2 in CD8 T cell fate determination comes from in vitro assessment of IL-2 production after restimulation of MPECs and SLECs, or through genetic ablation of IL-2. Hence, the ontogeny of IL-2 production capable MPECs and IL-2 non-producing SLECs remains ill-defined vis a vis their history of in vivo IL-2 production, and is confounded by thymic developmental effects or autoimmune side effects of germline il2 ablation. In this exploratory R21 proposal we have generated unique murine models of conditional il2 gene deletion (for specific ablation of autocrine IL-2 in post-thymic T cells), and IL-2 reporter system (for in vivo tracking of IL-2 production history of antigen-specific CD8 T cells). Using these innovative tools, we seek to resolve the enigma of how autocrine and paracrine IL-2 signals determine the polar life versus death decisions of MPECs and SLECs. Illumination of the signaling and transcriptional cascades downstream of autocrine and paracrine IL-2 signals may be exploited for innovating novel pharmacologic or immunologic interventions to shift the balance of effector and memory CTLs as defined by clinical needs.
摘要

项目成果

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Vandana Kalia其他文献

Vandana Kalia的其他文献

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{{ truncateString('Vandana Kalia', 18)}}的其他基金

Bispecific Antibody Therapeutics for Neuroblastoma and Diffuse Midline Glioma
用于神经母细胞瘤和弥漫性中线胶质瘤的双特异性抗体治疗
  • 批准号:
    10714915
  • 财政年份:
    2023
  • 资助金额:
    $ 23.25万
  • 项目类别:
Immune Aging in Responsiveness to Checkpoint Blockade Immunotherapies
免疫老化对检查点阻断免疫疗法的反应
  • 批准号:
    10674256
  • 财政年份:
    2022
  • 资助金额:
    $ 23.25万
  • 项目类别:
Differential IL-2 Expression by Effector CD8 T cells and Fate Determination
效应 CD8 T 细胞的差异 IL-2 表达和命运决定
  • 批准号:
    10263196
  • 财政年份:
    2020
  • 资助金额:
    $ 23.25万
  • 项目类别:
Regulation of CD8 T cell memory by autocrine IL-2
自分泌 IL-2 对 CD8 T 细胞记忆的调节
  • 批准号:
    8893289
  • 财政年份:
    2015
  • 资助金额:
    $ 23.25万
  • 项目类别:
CD8 T Cell Intrinsic Role of MicroRNA-17~92 in TCR Signaling
MicroRNA-17~92 在 TCR 信号转导中的 CD8 T 细胞内在作用
  • 批准号:
    8824047
  • 财政年份:
    2014
  • 资助金额:
    $ 23.25万
  • 项目类别:

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