T helper cell unresponsiveness: Rapid induction in antigen‐transgenic and reversion in non‐transgenic mice

AbstractT cell tolerance is usually established by clonal deletion of self‐specific T cells in the thymus, or some times, in the periphery. Alternatively, tolerance may also be achieved by induction of clonal T cell unresponsiveness by a poorly understood mechanism called “anergy”. We found that transgenic mice expressing a soluble form of vesicular stomatitis virus (VSV) glycoprotein (G) predominantly in liver and kidney exhibited normal B cell responses. VSV‐G‐specific T help‐independent neutralizing IgM responses were within normal ranges, but no T help‐dependent neutralizing IgG antibodies were generated upon immunization with recombinant VSV‐G protein and recombinant vaccinia virus expressing VSV‐G. This demonstrated absence of B cell tolerance but presence of T helper cell unresponsiveness. After adoptive transfer of transgenic spleen cells into thymectomized immuno‐incompetent hosts, the unresponsive T helper cells regained function and switched the neutralizing IgM response to IgG, comparably to control T helper cells, within 7 days. Conversely, when naive non‐transgenic spleen cells were transferred into transgenic mice, VSV‐G‐specific T helper cells became unresponsive within 3–4 days. These results suggest that VSV‐G‐specific T helper cells are rendered unresponsive within a few days in the VSV‐G transgenic host also outside of the thymus and that this unresponsiveness was reversed by transfer into antigen‐free recipients.