The following interview was conducted by Signals+ Editor Di Yu, Ph.D.
The Journal of Experimental Medicine (JEM) recently published the study by Benjamin J. Broomfield et. al. showing early, short-term inhibition of IFN-I optimizes TSCM cell differentiation. Broomfield is a Ph.D. candidate in the Joanna Groom lab at WEHI.
Highlights of the study include:
- CD8+ T cells primed in the absence of IFN-I signaling transition from precursor of exhausted (TPEX) to stem cell-like memory T (TSCM) cell states without establishing chronic infection.
- Established transcriptional and cell surface biomarkers to monitor the plasticity of TPEX and TSCM conversion, concordant with viral clearance.
- Transient IFNAR blockade increases IFNγ production to modulate the ligands of CXCR3, and couple TSCM cell differentiation to cell retention within the T cell paracortex of the lymph node.
- mRNA-LNP vaccination with IFN-I blocking drives TSCM formation to provide superior protection from chronic infection.
What we discovered
TCF-1+ stem-like CD8+ T cells are a key target for long-lived vaccine design and cancer immunotherapy. We set out to understand how these cells could be specifically enhanced in vivo. Early, transient inhibition of the type I IFN receptor (IFNAR) drove stem-like CD8+ T cell generation following viral infection and mRNA–lipid nanoparticle vaccination.
The use of early IFNAR blockade appeared to generate a hybrid setting for LCMV infection between acute and chronic conditions. We observed delayed viral clearance but this did not establish chronicity. Use of scRNAseq allowed us to identify that CD8+ T cells transitioned through a precursor of exhausted T (TPEX) cell phenotype before becoming stem cell-like memory T (TSCM) cells, with this transition aligning with viral clearance. We identified novel markers distinguishing TPEX and TSCM cell states, enabling us to track their plasticity in antigen rich and free environments. These findings provide key insights into the developmental relationship of different stem-like T cell states and the environmental cues that guide their conversion.
In the absence of IFN-I signaling, IFNγ was counter-intuitively increased to regulate CXCR3 chemokine expression. This disrupted the formation of chemokine gradients resulting in T cell retention in the lymph node paracortex, a location that highly correlated with stem-like formation.
Building on these insights, we combined IFNAR blockade with mRNA-LNP vaccination. Similar to infection, this increased antigen expression and drove TSCM cell formation. This led to enhanced protection against a secondary chronic viral challenge, characterized by increased CD8+ T cell number, reduced terminal exhaustion and rapid viral clearance.
Why it matters
The promotion of TCF-1+ stem-like cells is a major goal of prophylactic vaccines that elicit T cell memory and cancer therapeutic vaccines that promote tumor clearance. We establish the differentiation trajectory that promotes these cells and establish methods to track stem-like cell states during vaccination, infection, and immunotherapy.
Overall, our results propose a new approach to vaccine and adjuvant design whereby timed modulation of inflammatory and migration cues directs T cell memory formation and function.
Read the full paper
Check out the full paper online (and open access) in the Journal of Experimental Medicine here.