The role of CD4(+) T cell help and CD40 ligand in the in vitro expansion of HIV-1-specific memory cytotoxic CD8(+) T cell responses

CD4(+) T cells have been shown to play a critical role in the maintenance o f an effective anti-viral CD8(+) CTL response in murine models. Recent stud ies have demonstrated that CD4(+) T cells provide help to CTLs through liga tion of the CD40 receptor on dendritic cells, The role of CD4(+) T cell hel p in the expansion of virus-specific CD8(+) memory T cell responses was exa mined in normal volunteers recently vaccinated to influenza and in HIV-1 in fected individuals. In recently vaccinated normal volunteers, CD4(+) T cell help was required for optimal in vitro expansion of influenza specific CTL responses, Also, CD40 ligand trimer (CD40LT) enhanced CTL responses and wa s able to completely substitute for CD4(+) T cell help in PBMCs from normal volunteers. In HIV-1 infection, CD4(+) T cell help was required for optima l expansion of HIV-l-specific memory CTL in vitro in 9 of 10 patients. CD40 LT could enhance CTL in the absence of CD4(+) T cell help in the majority o f patients; however, the degree of enhancement of CTL responses was variabl e such that, in some patients, CD40LT could not completely substitute for C D4(+) T cell help. In those HIV-l-infected patients who demonstrated poor r esponses to CD40LT, a dysfunction in circulating CD8(+) memory T cells was demonstrated, which was reversed by the addition of cytokines including IL- 2, Finally, it was demonstrated that IL-15 produced by CD40LT-stimulated de ndritic cells may be an additional mechanism by which CD40LT induces the ex pansion of memory CTL in CD4(+) T cell-depleted conditions, where IL-2 is l acking.