How T Cells Maintain Long-Term Immunity

Scientists in the laboratory of Weiguo Cui, PhD, professor of Pathology in the Division of Experimental Pathology, have identified novel molecular mechanisms that help specialized T-cells maintain long-term immunity in response to chronic infection and cancer, according to recent findings published in Nature Immunology.  

Previous work from Cui’s laboratory and others revealed that exhausted T-cells, or T-cells that have become dysfunctional after chronic antigen stimulation such as chronic infection and cancer, comprise different subgroups of T-cells. 

One of these subgroups are stem-like progenitor CD8+ T-cells, which help sustain the body’s immune response through quiescence (when T-cells are dormant but at the ready to be activated by a foreign antigen), multipotency (the ability to differentiate into different cell types) and self-renewal. 

Better understanding how these T-cells preserve their stem-like qualities under persistent stimulation can help inform new strategies that enhance CD8+ T-cell response and the effectiveness of immunotherapies, according to Cui. 

“These cells are really in it for the long haul,” said Cui, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and the Center for Human Immunobiology. “We wanted to identify what other factors control the formation as well as long-term existence for this type of T-cell in our body.” 

In the current study, Cui and his team performed single-cell RNA sequencing on antigen-specific CD8+ T-cells isolated from mouse models of chronic infection. Using flow cytometry and immunoblotting techniques to study these cells, the scientists observed that the SATB1 protein is upregulated in progenitor and memory CD8+ T-cells. 

Next, the scientists used CRISPR gene editing to delete the SATB1 gene from the isolated CD8+ T-cells and discovered that SATB1 is essential for maintaining CD8+ T-cell “stemness” during chronic infection and for memory CD8+ T-cell formation during acute infection. Using multi-omic profiling, the investigators also found that SATB1 deficiency led to the downregulation of stemness-associated genes and the upregulation of cell differentiation genes. 

The findings reveal an essential role for SATB1 in regulating the transcriptional and epigenetic mechanisms underlying the stem-like properties of CD8+ T-cells and advance the understanding of how stemness is maintained in both acute and chronic infections. 

Moving forward, Cui said his team will continue to investigate the molecular mechanisms of SATB1 in this subset of immune cells, findings that may inform the development of more effective immunotherapy strategies. 

“We’re going to take on some 3D genome structure studies and identify where SATB1 really is doing this binding on the genome and to see how in the presence or absence of SATB1 the genomic architecture will change and how that actually contribute to their loss of their stemness. 

Reference: Lin S, Niu H, Zhang Y, et al. SATB1 is a key regulator of quiescence in stem-like CD8+ T cells. Nat Immunol. 2025:1-15. doi: 10.1038/s41590-025-02257-w

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