Mounting evidence suggests that the mechanisms that regulate T cell proliferation, acquisition of effector function, and memory cell formation and maintenance are different for CD4 and CD8 T cells. We compared the proliferation of adoptively transferred TCR transgenic CD4 and CD8 T cells in response to Listeria monocytogenes (LM) infection and found that CD4 T cells undergo limited division, differentiation, and clonal expansion in comparison to CD8 T cells. To further investigate these differences, we developed an adoptive transfer system that enables the visualization of primary polyclonal T cell responses. Surprisingly, we observed a difference in the extent of division between transferred monoclonal CD4 T cells and polyclonal CD4 T cells in response to LM infection. Adoptively transferred TCR transgenic CD4 T cells divided a limited number of times in response to LM infection while transferred CD4 T cells from C57BL/6 mice divided extensively under the same infection conditions. Titration of transferred TCR transgenic CD4 T cells revealed that reducing the precursor frequency increased the mean number of divisions underwent by these cells and increased the percent of responding CD4 T cells that differentiated into effector CD4 T cells as determined by IFN-γ secretion. Moreover, the transfer of a low number of naive TCR transgenic CD4 T cells provided better protection against LM infection in the liver than the transfer of a large number of the same cells. In contrast, adoptively transferred TCR transgenic CD8 T cells and polyclonal CD8 T cells from C57BL/6 mice both divided and differentiated extensively following infection. Thus, clonal competition induced by abnormally high precursor frequencies limits the extent of division and differentiation of CD4 T cells more than CD8 T cells. These results also show that CD4 T cell division and differentiation is quite extensive in response to LM infection and that the adoptive transfer of TCR transgenic CD4 T cells may underestimate the extent of a natural CD4 T cell response. However, despite this robust response, our data indicates that CD4 T cells provide only limited protection against LM infection in comparison to CD8 T cells
