Jean-Christophe Beltra

"A role for the transcription factor STAT5 in antagonizing CD8+ T cell exhaustion"

Beltra, JC and E. John Wherry

Exhaustion gradually establishes in chronically stimulated CD8s and this process is not reverted by current therapeutic approaches due to establishment of a stable epigenetic program. Recent advances have informed on the developmental process of exhaustion and highlighted TOX as a key lineage-defining TF in the process. Yet, little remains known on molecular pathways capable of antagonizing the TOX-dependent exhaustion program. By depicting transcriptional changes at key developmental steps of exhaustion, we demonstrate an antagonistic role for the TF STAT5 in the development of CD8 T cell exhaustion. STAT5 transcriptional network is heavily silenced upon chronic antigenic stimulation in a TOX-dependent manner which allows initiation of the exhaustion lineage. Increasing STAT5 activity abrogates establishment of the exhaustion lineage leading to the development of effector-like CD8s that acquire a unique transcriptional identity, distinct from exhausted cells, persist throughout chronicity and demonstrate higher protective capacity. Using temporal loss and gain of function approaches, we show that STAT5 triggers loss of progenitor identity by exhausted CD8s (Tex) and subsequent differentiation into the recently identified effector-like intermediate Tex subset. Stronger temporal re-activation of STAT5 in established Tex cells may even re-wire these cells into a more effector-like state. Together, we show that modulating STAT5 activity may counteract the exhaustion process and favor instigation of effector-like characteristic in Tex cells suitable for optimal therapeutic efficacy.
 
This work is supported by NIH grants AI155577 and AI149680. JC-Beltra is a Parker Institute for Cancer Immunotherapy scholar awardee.