TLR9 Sensing of Self-DNA Controls Cell-Mediated Immunity to Listeria Infection via Rapid Conversion of Conventional CD4+ T Cells to Treg

Abstract

CD4⁺ T lymphocytes are crucial for controlling a range of innate and adaptive immune effectors. For CD8⁺ cytotoxic T lymphocyte (CTL) responses, CD4⁺ T cells can function as helpers (T_H) to amplify magnitude and functionality or as regulatory cells (T_reg) capable of profound inhibition. It is unclear what determines differentiation to these phenotypes and whether pathogens provoke alternate programs. We find that, depending on the size of initial dose, Listeria infection drives CD4⁺ T cells to act as T_H or induces rapid polyclonal conversion to immunosuppressive T_reg. Conversion to T_reg depends on the TLR9 and IL-12 pathways elicited by CD8α⁺ dendritic cell (DC) sensing of danger-associated neutrophil self-DNA. These findings resolve long-standing questions regarding the conditional requirement for T_H amongst pathogens and reveal a remarkable degree of plasticity in the function of CD4⁺ T cells, which can be quickly converted to T_regin vivo by infection-mediated immune modulation.