Reduced functional avidity promotes central and effector memory CD4 T cell responses to tumor-associated antigens

The effect of TCR signals on the differentiation of memory T cells is poorly defined. Conventional wisdom suggests that high-avidity interactions are best for the selection of vaccine Ag candidates or T cell specificities for adoptive T cell therapy to stimulate robust responses. However, in conditions of Ag persistence, high-avidity clones might exhaust and fail to form long-lived protective memory. We have manipulated the functional avidity of CD4 T cells by reducing expression of Lck, a key kinase involved in TCR triggering. Using a mouse model, we followed tetramer-positive T cells responding to a tumor Ag expressed by an adenocarcinoma. We show that reducing the functional avidity increased effector-effector memory responses and improved the generation of selfrenewing, recirculating, tumor Ag-specific memory phenotype CD4 T cells. Moreover, such cells together with wild type CD8 T cells were better able to control tumor growth. Mechanistically, reducing Lck prolonged IL-2 production and cell turnover in the central memory population while reducing expression of exhaustion markers in the face of chronic Ag. Our data indicate that, in situations of persistent Ag challenge, generating T cells with reduced functional avidity may elicit more effective immune responses.