Th1 and Th2 Cell Clones to a Poorly Immunogenic Tumor Antigen Initiate CD8 ⁺T Cell-Dependent Tumor Eradication In Vivo

Although in vivo priming of CD8+ cytotoxic T lymphocytes (CTLs) generally requires the participation of CD4+ T-helper lymphocytes, the nature of the 'help' provided to CTLs is unknown. One widely held view is that help for CTLs is mediated by cytokines produced by T-helper cells activated in proximity to the CTL precursor at the surface of an antigen-presenting cell (APC). An alternative theory is that, rather than being directly supplied to the CTL by the helper cell, help is delivered through activation of the APC, which can then prime the CTL directly. CD40 and its ligand, CD40L, may activate the APC to allow CTL priming. CD40L is expressed on the surface of activated CD4+ T-helper cells and is involved in their activation and in the development of their effector functions. Ligation of CD40 on the surface of APCs such as dendritic cells, macrophages and B cells greatly increases their antigen-presentation and co-stimulatory capacity. Here we report that signalling through CD40 can replace CD4+ T-helper cells in priming of helper-dependent CD8+ CTL responses. Blockade of CD40L inhibits CTL priming; this inhibition is overcome by signalling through CD40. CD40-CD40L interactions are therefore vital in the delivery of T-cell help for CTL priming.

To generate an immune response, antigen-specific T-helper and T-killer cells must find each other and, because they cannot detect each other's presence, they are brought together by an antigen-loaded dendritic cell that displays antigens to both. This three-cell interaction, however, seems nearly impossible because all three cell types are rare and migratory. Here we provide a potential solution to this conundrum. We found that the three cells need not meet simultaneously but that the helper cell can first engage and 'condition' the dendritic cell, which then becomes empowered to stimulate a killer cell. The first step (help) can be bypassed by modulation of the surface molecule CD40, or by viral infection of dendritic cells. These results may explain the long-standing paradoxical observation that responses to some viruses are helper-independent, and they evoke the possibility that dendritic cells may take on different functions in response to different conditioning signals.

The induction of optimal systemic antitumor immunity involves the priming of both CD4+ and CD8+ T cells specific for tumor-associated antigens. The role of CD4+ T helper cells (Th) in this response has been largely attributed to providing regulatory signals required for the priming of major histocompatibility complex class I restricted CD8+ cytolytic T lymphocytes, which are thought to serve as the dominant effector cell mediating tumor killing. However, analysis of the effector phase of tumor rejection induced by vaccination with irradiated tumor cells transduced to secrete granulocyte/macrophage colony-stimulating factor indicates a far broader role for CD4+ T cells in orchestrating the host response to tumor. This form of immunization leads to the simultaneous induction of Th1 and Th2 responses, both of which are required for maximal systemic antitumor immunity. Cytokines produced by these CD4+ T cells activate eosinophils as well as macrophages that produce both superoxide and nitric oxide. Both of these cell types then collaborate within the site of tumor challenge to cause its destruction.