Role of Ufl1 in CD8+ Memory T Cell Survival and Function

Abstract

Immunity mediated by CD8+ T cells plays an integral part of the response to eradicate both infections and tumor cells. The recognition of antigen by the T cell receptor triggers a cascade of signaling events in naïve CD8+ T cells that leads to their proliferation and differentiation into memory and effector cells. Cytotoxic effector CD8+ T cells produce large amount of cytokines and effector molecules that play a critical role in the elimination of pathogens. Following pathogen clearance, a small population of memory T cells persists long-term, which has the ability to expand robustly upon re-exposure to antigen and provide the host with rapid and specific recall responses against the pathogen.

Treatments boosting an individual’s own immune response have changed the landscape of cancer research. However there are still limitations with patient responsiveness, toxic side effects, and not achieving long-term remission. As advances in immunotherapy revolutionize cancer treatment, understanding the molecular networks governing CD8+ T cell function has become more important than ever.

In our studies, we found that genetic knockout of UFM1 Specific Ligase 1 (Ufl1) in T cells leads to a CD8-specific loss of central memory cells. Flow cytometry staining revealed that the population of CD8+CD122+ T cells are significantly reduced in mice lacking Ufl1 in T cells. We observed that Ufl1 deficiency leads to apoptosis of these cells in vivo. Ufl1-deficient CD8+CD122+ T cells express higher amounts of Fas on the cell surface as well as activated cleaved caspase 3. RNA-sequencing analysis demonstrated that these cells also overexpress numerous genes associated with exhaustion, including PD-1, Lag3, Tim3, and 2B4. Interestingly, the Listeria monocytogenes disease model showed that Ufl1-deficient CD8+ T cells behave similarly to wild type cells during the acute effector response, but undergo a more dramatic contraction and subsequently launch an attenuated recall response. Consistent with this, a melanoma-specific vaccine failed to protect mice lacking Ufl1 in T cells. Our present study suggests that Ufl1 plays a critical role in the suppression of apoptosis and exhaustion of memory CD8+ T cells.