Amazing stuff!
"T cells are positioned at the frontline of the body’s immune system to fight infection, cancer, and autoimmune disease. While different subtypes of T cells exist, how these cells take their different forms has remained elusive.
Now, ... researchers ... has added clarity to the complex, dynamic molecular interactions that occur in the human immune system. In a new study, the researchers have identified one of the levers that controls the fate of T cells and what subtype they transform into. ...
One type of T cell—known as a CD8—is constantly on the prowl in the human body in search of intruders that can cause infections and disease. CD8 T cells transform, or differentiate, at different stages of the immune response. During the normal process, these cells can become either activated killers that destroy infected cells or memory cells that contain the recipe to relaunch a defense against future infections. But they can also slip into dysfunctional, or “exhausted,” states that make them less effective in an immune response. ...
The research team found that a protein called Kruppel-like factor 2 (KLF2) was the only one they tested that pushed the T cells along an unexpected path. It was known that KLF2 controlled where the cells go in the body, but the team found KLF2 also acted like a lever, regulating the differentiation of CD8 cells. ..."
From the editor's summary and abstract:
"Editor’s summary
CD8 T cells within a population responding to signs of disease can form several discrete states with distinct functional properties. Fagerberg et al. combined CRISPR/Cas9-gene editing with single-cell RNA sequencing to examine how the deletion of genes in mouse T cells affected the formation of these different states during immune responses.
The transcription factor KLF2 was required to maintain the availability of cells with the potential to form functional effectors and suppressed cells from acquiring an exhausted phenotype after infection with acute lymphocytic choriomeningitis virus. In the context of tumors, KLF2 expression was linked to maintaining stem-like T cells and limiting terminal dysfunction. ...
Structured Abstract
INTRODUCTION
Naïve CD8 T cells have the potential to differentiate into a variety of effector and memory CD8 T cell states during an immune response. These states reflect the cells’ functional potential to fight infection, respond to immunotherapies, or cause immunopathology. Acute T cell responses are associated with highly functional effector and memory states.
Conversely, chronic antigen environments, as seen in tumors and chronic infection, drive dysfunctional T cell fate decisions, termed generally as T cell exhaustion.
RATIONALE
Despite recent insights into how these divergent T cell differentiation states determine physiological outcomes, it remains uncertain how fate decisions are made and what mechanisms exist to suppress differentiation towards alternative fates and maintain lineage fidelity. ... PerturbSEQ is a technique that couples CRISPR perturbations of target genes with single-cell RNA sequencing (scRNA-seq) and enables mechanistic dissection of differentiation processes. In this study, we used perturbSEQ with the goal of understanding factors that regulate fate decisions and preserve T cell lineage fidelity.
RESULTS
We generated a differentiation space map (DSM) of the spectrum of CD8 T cell states in acute and chronic lymphocytic choriomeningitis virus (LCMV) infection across time points using scRNA-seq.
Analyses across four time points revealed a linear differentiation trajectory in acute infection, whereas a bifurcation between effector and exhausted trajectories was observed in chronic infection. We then performed in vivo perturbSEQ in LCMV-specific CD8 T cells for a library of ~40 genes [largely transcription factors (TFs) and epigenetic modulators] in the context of acute LCMV infection. This experiment identified proteins that could regulate the extent to which cells differentiated along an expected memory to effector trajectory, thereby highlighting their role as a suppressor or promoter of specific T cell functions.
Moreover, it elucidated KLF2 as a transcription factor that maintains effector lineage fidelity. KLF2 knockout (KO) T cells aberrantly acquired distinct features of exhaustion during acute LCMV infection. This included impaired effector and memory differentiation and function during both primary and secondary viral challenge. Epigenetic changes, both at sites of KLF2 binding and globally throughout the genome, overlapped with loci accessibility changes seen in chronic infection.
Mechanistic studies showed that KLF2 was downregulated upon T cell receptor stimulation and was intrinsically required for suppression of the exhaustion-defining TF, TOX. Epistasis experiments revealed that KLF2 was also critical for enabling the function of the effector-defining TF, TBET. Investigation in tumor models pointed to a role for KLF2 in the early bifurcation of effector and exhausted differentiation trajectories as KLF2 was required to maintain a polyfunctional TCF1+ CD62L+ precursor state. KO cells less potently controlled tumors and exhibited enhanced differentiation with features of exhaustion and residence. Overexpression of KLF2 was sufficient to rescue this precursor state in tumor-draining lymph nodes as well as suppress features of exhaustion and induce effector differentiation in acute and chronic viral infection.
CONCLUSION
Our study highlighted the role of many TFs in regulating the extent to which CD8 T cells differentiate along a defined linear trajectory and revealed KLF2’s distinct role in enabling cells to remain on this effector lineage. This adds to our mechanistic understanding of T cell fate decisions and demonstrates that differentiation toward the exhaustion lineage is suppressed in acute infection. It additionally opens new questions regarding maintenance of lineage fidelity across immune contexts, where little is still known. Further, modulation of KLF2 proved useful in driving or suppressing distinct T cell functional states with potential implications for immunotherapy."
KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection (no public access)
KLF2 prevents aberrant CD8 T cell differentiation in acute LCMV infection.
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