CD4+ T cells support cytotoxic T lymphocyte priming by controlling lymph node input

Rapid induction of CD8(+) cytotoxic T lymphocyte (CTL) responses is critical to combat acute infection with intracellular pathogens. CD4(+) T cells help prime antigen-specific CTLs in secondary lymphoid organs after infection in the periphery. Although the frequency of naive precursors is very low, the immune system is able to efficiently screen for cognate CTLs through mechanisms that are not well understood. Here we examine the role of CD4(+) T cells in early phases of the immune response. We show that CD4(+) T cells help optimal CTL expansion by facilitating entry of naive polyclonal CD8(+) T cells into the draining lymph node (dLN) early after infection or immunization. CD4(+) T cells also facilitate input of naive B cells into reactive LNs. Such help involves expansion of the arteriole feeding the dLN and enlargement of the dLN through activation of dendritic cells. In an antigen-and CD40-dependent manner, CD4(+) T cells activate dendritic cells to support naive lymphocyte recruitment to the dLN. Our results reveal a previously unappreciated mode of CD4(+) T-cell help, whereby they increase the input of naive lymphocytes to the relevant LN for efficient screening of cognate CD8(+) T cells.