Multiple paths for activation of naive CD8(+) T cells: CD4-independent help

CD8(+) CTLs play a pivotal role in immune responses against many viruses an d tumors. Two models have been proposed. The "three-cell" model focuses on the role of CD4(+) T cells, proposing that help is only provided to CTLs by CD4(+) T cells that recognize Ag on the same APC. The sequential "two-cell " model proposes that CD4(+) T cells can first interact with APCs, which in turn activate naive CTLs. Although these models provide a general framewor k for the role of CD4(+) T cells in mediating help for CTLs, a number of is sues are unresolved. We have investigated the induction of CTL responses us ing dendritic cells (DCs) to immunize mice against defined peptide Ags. We find that help is required for activation of naive CTLs when DCs are used a s APCs, regardless of the origin or MHC class I restriction of the peptides we studied in this system. However, CD8(+) T cells can provide self-help i f they are present at a sufficiently high precursor frequency. The importan t variable is the total number of T cells responding, because class II-knoc kout DCs pulsed with two noncompeting peptides are effective in priming.