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Regulation of T cell activation and proliferation through cell-intrinsic cytoskeletal elements and cell-extrinsic cellular interactions

  • Author(s): Mujal, Adriana
  • Advisor(s): Krummel, Matthew F
  • Weiss, Arthur
  • et al.
Abstract

An efficacious immune response requires both rapid clonal expansion of activated T cells and homeostatic turnover to maintain the T cell compartment. These various proliferative processes are driven by different stimuli such as T cell receptor signaling or cytokines that act independently or synergistically. Although it has been thought that these distinct cues result in similar use of cellular machinery to undergo cell division, we found that CD8+ T cell division selectively requires the septin cytoskeleton depending on the stimulus condition. Septin-deficient CD8+ T cells undergo robust proliferation when activated by antigen-presenting cells (APCs) that provide co-stimulatory PI3K signaling, but these T cells exhibit cytokinetic failure following cytokine-driven division. This differential requirement for septins reveals previously unrecognized complexity of T cell proliferation with the potential for therapeutic modulation of context-specific T cell expansion.

As specialized APCs, dendritic cells (DCs) play a central role in initiating and guiding antigen-specific T cells responses. For example, in the setting of cancer, a pro-stimulatory CD103+ DC population has been identified as required for driving effector CD8+ T cell activity. In addition to targeting CD8+ T cells, therapeutic modulation of effector CD4+ T cells may too have clinical benefit in augmenting anti-tumor responses. It has been unclear, however, which myeloid population is predominantly involved in initial priming of CD4+ T cells. To address this diversity in DC populations that participate in anti-tumor responses, we have employed single-cell RNA-sequencing to investigate the heterogeneity present in the lymph node (LN) myeloid compartment and to better understand the migratory DC populations that traffic from the tumor to the local draining LN. From this, we have used a combination of in vivo and in vitro assays to identify multiple tumor-antigen bearing CD11b+ DCs subsets in the lymph nodes that can contribute to anti-tumor T cell response.

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