Following an RNAseq-based targeted search for novel CD8+ T cell surface markers of exhaustion in the well-studied LCMV system, Hudson et al. found that CD101 expression could be used to distinguish two trajectory-related populations following stimulation of antigen-specific PD-1+Tcf-1+ stem cells. A CD101-Tim3+CX3CR1+ population arose first, characterized by high proliferative capacity, functional capability, and ability to control viral load, followed in 2-4 weeks by CD101+Tim3+CX3CR1- terminally exhausted cells with low proliferative and functional capacity. PD-1 blockade significantly enhanced expansion of the effector CD101- population.
T cell dysfunction is a characteristic feature of chronic viral infection and cancer. Recent studies in chronic lymphocytic choriomeningitis virus (LCMV) infection have defined a PD-1+ Tcf-1+ CD8+ T cell subset capable of self-renewal and differentiation into more terminally differentiated cells that down- regulate Tcf-1 and express additional inhibitory molecules such as Tim3. Here, we demonstrated that expression of the glycoprotein CD101 divides this terminally differentiated population into two sub- sets. Stem-like Tcf-1+ CD8+ T cells initially differenti- ated into a transitory population of CD101Tim3+ cells that later converted into CD101+ Tim3+ cells. Recently generated CD101Tim3+ cells proliferated in vivo, contributed to viral control, and were marked by an effector-like transcriptional signature including expression of the chemokine receptor CX3CR1, pro-inflammatory cytokines, and granzyme B. PD-1 pathway blockade increased the numbers of CD101Tim3+ CD8+ T cells, suggesting that these newly generated transitional cells play a critical role in PD-1-based immunotherapy."
