Blane, T. | Search bioRxiv

bioRxiv2025

Lack of Bcl6 promotes anti-tumor immunity by activating glycolysis to rescue CD8 T cell function

T cells are one of the most powerful weapons to fight cancer; however, T cell exhaustion and dysfunction restrict their long-lasting function in anti-tumor immunity. B-cell lymphoma 6 (BCL6) has many functions in CD8 T cells but it is unclear how it regulates the effector function and exhaustion of CD8 cells. Overall, a low level of BCL6 mRNA in human cancer samples is associated with better outcomes. We found that BCL6 deficiency in activated CD8 T cells enhanced tumor repression in multiple mouse models. More IL-2-expressing CD8 T cells and reduced proportions of exhausted or dysfunctional CD8 T cells were detected within tumors when Bcl6 was knocked out upon T cell activation. Glycolysis was promoted in BCL6-deficient CD8 T cells owing to derepression of glucose transporter GLUT3 (encoded by Slc2a3). The BCL6 inhibitor Fx1 promoted anti-tumor immunity in a T cell-dependent manner. These findings suggest a novel pathway to restore effector function of CD8 T cells by changing their energy utilization pathways to facilitate long-term tumor resistance. Summary BlurbBCL6 limits CD8 T cell responses to tumors by inhibiting Glut3 expression. Conditional deletion of Bcl6 in activated CD8 T cells or pharmacological inhibition of BCL6 in mice represses tumor growth.

immunology↗

bioRxiv2020

B cells expressing authentic naive human VRC01-class BCRs can be primed and recruited to germinal centers in multiple independent mouse models

Animal models of human antigen-specific B cell receptors (BCR) generally depend on "inferred germline" sequences, and thus their relationship to authentic naive human B cell BCR sequences and affinities is unclear. Here, BCR sequences from authentic naive human VRC01-class B cells from healthy human donors were selected for the generation of three new BCR knock-in mice. The BCRs span the physiological range of affinities found in humans, and use three different light chains (VK3-20, VK1-5, and VK1-33) found among subclasses of naive human VRC01-class B cells and HIV broadly neutralizing antibodies (bnAbs). The germline-targeting HIV immunogen eOD-GT8 60mer is currently in clinical trial as a candidate bnAb vaccine priming immunogen. To attempt to model human immune responses to the eOD-GT8 60mer, we tested each authentic naive human VRC01-class BCR mouse model under rare human physiological B cell precursor frequency conditions. B cells with high (HuGL18HL) or medium (HuGL17HL) affinity BCRs were primed, recruited to germinal centers, accrued substantial somatic hypermutation, and formed memory B cells. Precursor frequency and affinity interdependently influenced responses. Taken together, these experiments utilizing authentic naive human VRC01-class BCRs validate a central tenet of germline-targeting vaccine design and extend the overall concept of the reverse vaccinology approach to vaccine development.

immunology↗