Chronic Lymphocytic Leukemia Induces Skewing of Antigen-Specific T-cell Responses Towards a Dysfunctional Short-Lived Effector Phenotype
The TCL1 mouse model displays similar features of T-cell dysfunction as observed in chronic lymphocytic leukemia (CLL) patients and provides an excellent model to study antigen-specific CD8+ T-cell response in the context of CLL.
We developed a model to study antigen-specific responses in the TCL1 adoptive transfer model. Following development of leukemia, mice were injected with OT-I cells and infected with mCMV-OVA.
Seven days after infection, we observed skewing of both the endogenous CD8 compartment as well as the adoptively transferred OT-I cells towards a short-lived effector phenotype (KLRG1+CD127-) in CLL mice compared to wild-type mice. This was associated with enhanced expression of the effector-associated transcription factor T-bet, and reduced expression of memory-associated transcription factor Bcl-6. Restimulation of OT-I cells resulted in decreased cytokine production and degranulation of the CLL derived OT-I cells. These phenotypic and functional characteristics were accompanied by genome-wide chromatin remodeling and altered gene expression profiles, which will be further presented during the meeting.
Our results demonstrate that there is a CLL-dependent effect on acute (non-CLL) antigen-specific immune responses, driving T-cells towards a functionally impaired effector phenotype. This study provides clues for better understanding T-cell responses dysfunction in CLL, possibly leading to improved T-cell therapy.