Date of Award

5-2024

Document Type

Thesis (Ph.D.)

Department or Program

Microbiology and Immunology

First Advisor

Yina H. Huang

Abstract

Generating balanced populations of CD8 effector and memory T cells is necessary for immediate and durable immunity to infections and cancer. Yet, a definitive understanding of CD8 differentiation remains unclear. Here we used CARLIN, a processive lineage recording mouse model with single-cell RNA-seq and TCR-seq to track endogenous antigen-specific CD8 T cells during acute viral infection.

Transcriptional profiling of antigen-specific T cells at the peak of the effector response to Vesicular stomatitis virus uncovered a diverse repertoire of expanded antigen-specific T-cell clones represented by seven transcriptional states. TCR enrichment analysis identified TCR clones with differential memory- or effector-fate biases during the peak of the effector phase. Shared Vb segments and amino acid motifs were found within TCR biased categories despite high overall TCR diversity. Using single-cell CARLIN barcode-seq we tracked multi-generational TCR clones and found that unlike unbiased or memory-biased TCR clones, which stably retain their fate profiles, effector-biased TCR clones could adopt memory- or effector-bias within subclones. Using TCR retrogenic mice we validated the fate commitment of one effector biased TCR clone and two memory biased TCR clones. These biased clones also maintained their lineage preference under different inflammatory cues that had previously been reported to alter T cell fate. We also demonstrate that TCRs identified in the effector phase to be memory biased were able to promote antigen-driven CD8 T cell differentiation into multiple long-lived memory subsets in response to an acute viral infection.

Moreover, the observed TCR bias in cell fate commitment was not limited to the effector response as our transcriptional and TCR enrichment analysis of antigen-specific CD8 T cells at a memory timepoint also revealed long-lived effector (LLEC) biased, effector memory (TEM) biased and tissue resident memory (TRM) biased TCR clones. Shared Vb segments were found in the LLEC and TEM biased TCRs while TRM biased clones preferred a unique set of Vb segments. Collectively, our study demonstrates that a heterogenous T-cell repertoire specific for a shared antigen is composed of clones with distinct TCR-intrinsic fate biases.

Original Citation

Abdullah, L., Emiliani, F. E., Vaidya, C. M., Stuart, H., Kolling, F. W., Ackerman, M. E., Song, L., McKenna, A., & Huang, Y. H. (2024). Hierarchal single-cell lineage tracing reveals differential fate commitment of CD8 T-cell clones in response to acute infection. bioRxiv : the preprint server for biology, 2024.03.21.586160. https://doi.org/10.1101/2024.03.21.586160

Download

Included in

Immunity Commons

Share

COinS