Heterospecific CD4 Help to Rescue CD8 T Cell Killers

Abstract

Help from CD4 T cells may be required for optimal generation and maintenance of memory CD8 T cells and also for optimal Ag reactivation. We examined whether the helper cell and the CD8 killer cell need to have the same Ag specificity for help to be effective during interactions of memory T cells with mature APC. This is important because virus and tumor Ag-specific CD4 T cell responses are selectively impaired in several chronic viral infections and malignancies. We performed studies in vitro and in vivo and found that functional memory CD4 T cells generated from a distinct antigenic source (heterospecific helpers) could provide direct and effective help to memory CD8 T cells. Functional heterospecific memory CD4 T cells could also rescue secondary CD8 T cell responses in an experimental tumor model in which homospecific CD4 help was impaired. This could provide a rationale for immunotherapy strategies designed to bypass impaired homospecific help.

Direct CD4 Help Provision following Interaction of Memory CD4 and CD8 T Cells with Distinct Antigen-Presenting Dendritic Cells

“…Lewis lung carcinoma (LLC) cells were obtained from American Type Culture Collection (ATCC; Manassas, VA) and were cultured as previously described (10). LLC tumor lysates were prepared as outlined before (10).…”

“…LLC tumor lysates were prepared as outlined before (10). Male apoptotic splenocytes, obtained by osmotic shock, were used as a source of male Ag.…”

“…Two weeks later, 10 5 LLC cells were injected s.c. in the left flank. Then, 10-12 d later, when the tumor was palpable, the mice received an s.c. injection in the right flank of 5 3 10 5 Ag-loaded mature BMDCs prepared as follows: Immature BMDCs were loaded for 3 h with 10 mM OVA 323-339 and/or 100 mg/ml LLC tumor lysate, then washed and matured for 24 h with LPS (0.5 mg/ml).…”

“…Granzyme B expression was analyzed on CD8 + Uty + cells. In tumor experiments, Granzyme B + tumorinfiltrating CD8 T cells were evaluated as previously described (10). In some experiments, the following neutralizing Abs were used at 10 mg/ml: anti-IL-7, anti-IL-15, anti-CD40L, anti-LFA-1 (all from eBioscience), anti-IL-2, and anti-IL-21 (from R&D Systems).…”

“…Help from CD4 T cells appears to be necessary at the time of initial antigenic activation of naive CD8 T cells (2,3), and CD4 T cells may also be required for longterm maintenance of memory CD8 T cells after Ag eradication (2)(3)(4). Deficient secondary CD8 T cell responses have also been reported when CD4 T cells are lacking at the time of Ag reactivation of memory CD8 T cells (5)(6)(7)(8)(9)(10), even if the CD8 T cells are generated in normal help conditions (5)(6)(7)(8)(9)(10). The nature of the help provided by CD4 T cells during priming of naive CD8 T cells and during maintenance or reactivation of memory cells is largely unknown and may differ in these three situations.…”