Functional Genomics Of Immune Cells

We actively develop and apply CRISPR-based genome editing methods to identify genes and regulatory programs impacting immune cell fate and function. The lab is particularly interested in T cells, but we are extending our methodologies to other immune cell types including B cells and myeloid cells.

Human T cells are critical effectors of the immune response as well as autoimmune disease and are attractive tools for cancer immunotherapy. The lab has developed CRISPR-based methods for functional genomic screens identifying genes and networks crucial to the development, fate, and function of human T cells, as well as extending these efforts to other immune cell types.

We developed a method, sgRNA lentiviral infection with Cas9 protein electroporation (SLICE), for genome-wide CRISPR screens in human T cells. We have applied SLICE to discover targets that tune T cell responses to stimulation and immunosuppression and coupled SLICE with single-cell RNA-seq to reveal altered gene expression programs in targeted cells. We recently published a complementary strategy to barcode and track targeted integrations of large DNA templates, enabling pooled knock-in screens in primary human T cells, revealing natural and synthetic sequences that reprogram T cell functions. These technologies allow us to thoroughly investigate the genetic programs that control human immune cell identity and function, adding to our understanding of disease genetics and nominating candidates for therapeutic development.

Selected Publications

RASA2 ablation in T cells boosts antigen sensitivity and long-term function
Nature, 2022
CRISPR activation and interference screens decode stimulation responses in primary human T cells
Science, 2022
Pooled Knockin Targeting for Genome Engineering of Cellular Immunotherapies
Cell, 2020
Functional CRISPR dissection of gene networks controlling human regulatory T cell identity
Nature Immunology, 2020
CRISPR screen in regulatory T cells reveals modulators of Foxp3
Nature, 2020
Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function
Cell, 2018


Media highlights of Alex and the lab’s research.
How Unique Immune Cells Can Recognize—and Destroy—Tumors
Giving Immunotherapy Cells Resilience to Pass the ‘Stress Test’
Gene Editing Expands to New Types of Immune Cells
Genetic Network that Differentiates Regulatory T Cells Mapped
Scientists map genes controlling immune system “brakes”