Wednesday, May 8, 2024
5/8/2024
Summary Although it is becoming increasingly clear that CD8 T cells responding to chronic infection are phenotypically and functionally diverse, little is known about how to overcome T cell exhaustion to treat infectious diseases. Using single cell RNA sequencing (scRNA-seq), the investigator's team has confirmed the presence of previously identified TCF-1hi progenitor and PD-1hi exhausted T subsets. Surprisingly, they also found a CX3CR1+ effector subset at the late phase of chronic infection. More importantly, they have shown that CX3CR1+ effector cell formation is critically dependent on IL-21-producing CD4 helper T cells. The discovery of this potent antiviral effector subset provides new opportunities for therapeutic interventions to treat infectious diseases. To better understand the genesis of CX3CR1+ effector cells, the investigator's team proposes to use the newly developed technology of paired single-cell RNA and TCR sequencing (scTCR-seq) to “lineage trace” back to the ancestors (progenitors) of effector and exhausted cells. Their preliminary data suggest that TCR signaling strengths positively correlate with exhausted T cell subset differentiation, but negatively correlate with effector T cell differentiation. In parallel, they also provide evidence that CX3CR1+ effector cell formation depends on cross-presenting dendritic cells (DCs), especially Batf3+ XCR1+ cDC1s. These cDC1 cells are likely subjected to CD40-mediated CD4 helper T cell licensing, which is unexpected in the context of persistent infection and possibly occurs in specialized cellular structures. Taken together, the investigator hypothesizes that progenitor CD8 T cells need to be primed and activated by the cDC1s again at the late phase of chronic infection to enter into a proliferative burst as a transitory differentiation state, and then bifurcate into two terminally differentiated subsets: CX3CR1+ effector and PD-1hi exhausted CD8 T cells. Mechanistically, CD4 T cells need to provide signals to license DCs for their cross-presentation, and TCR signaling strength dictates the threshold of progenitor cell activation and influences the effector versus exhausted cell fate choice. Harnessing this knowledge, they intend to alter the course of T cell differentiation by changing TCR signaling strength through identification and validation of TCR signaling negative regulators (TSNRs) that can be exploited to favor the formation of CX3CR1+ effector T cells for improved viral control. The investigator's team will test these hypotheses in the following three aims. First, they will use paired scRNA- and scTCR- seq and associated computational tools and biological validations to delineate virus-specific CD8+ T cell differentiation trajectories and dissect how TCR signaling strength affects cell fate decisions. Second, they will use genetic models to delineate the mechanisms by which DCs are licensed by CD4 helper T cells for CD8 T cell priming and differentiation. Third, they will employ high-throughput targeted CRISPR screen and gene editing to test if manipulating TCR signaling strength can redirect CD8 T cells towards effector differentiation and overcome exhaustion to treat chronic infection and cancer.
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