The viral context instructs the redundancy of costimulatory pathways in driving CD8 ⁺ T cell expansion

Abstract

Signals delivered by costimulatory molecules are implicated in driving T cell expansion. The requirements for these signals, however, vary from dispensable to essential in different infections. We examined the underlying mechanisms of this differential T cell costimulation dependence and found that the viral context determined the dependence on CD28/B7-mediated costimulation for expansion of naive and memory CD8 ⁺ T cells, indicating that the requirement for costimulatory signals is not imprinted. Notably, related to the high-level costimulatory molecule expression induced by lymphocytic choriomeningitis virus (LCMV), CD28/B7-mediated costimulation was dispensable for accumulation of LCMV-specific CD8 ⁺ T cells because of redundancy with the costimulatory pathways induced by TNF receptor family members (i.e., CD27, OX40, and 4-1BB). Type I IFN signaling in viral-specific CD8 ⁺ T cells is slightly redundant with costimulatory signals. These results highlight that pathogen-specific conditions differentially and uniquely dictate the utilization of costimulatory pathways allowing shaping of effector and memory antigen-specific CD8 ⁺ T cell responses.

DOI: http://dx.doi.org/10.7554/eLife.07486.001

eLife digest

When the immune system detects a virus in the body it mounts a response to eliminate it. Immune cells called CD8 ⁺ T cells detect fragments of virus proteins that are presented on the surface of other immune cells. The CD8 ⁺ T cells then rapidly divide to form populations that roam the body to kill cells that are infected with the virus. Afterwards, some of the CD8 ⁺ T cells become ‘memory T cells’, which allow the immune system to respond more rapidly if the virus returns. This means that a subsequent infection of the same virus is usually stopped before it can become severe enough for an individual to feel unwell.

Vaccines take advantage of the activities of CD8 ⁺ T cells to enable a person to become ‘immune’ to a virus without having to experience the disease. Vaccines contain dead or weakened viruses that can't spread in the body, but are able to activate the CD8 ⁺ T cells. However, a vaccine may not be as effective in activating the T cells as the live virus, perhaps because it fails to trigger the production of other molecules in the host that promote T cell activation. There are many of these ‘co-stimulatory molecules’ in the body, but it is not clear exactly how they work.

Now, Welten et al. show that the role of co-stimulatory molecules in the activation of CD8 ⁺ T cells depends on the type of virus and how it affects cells. Mice that were genetically engineered to lack two co-stimulatory molecules called CD80 and CD86 failed to accumulate active CD8 ⁺ T cells in response to infection with a herpes-like virus. However, if these mice were infected with a different virus called LCMV—which causes swelling of the brain and spinal cord—they produced many active CD8 ⁺ T cells to fight the infection.

Welten et al. found that other co-stimulatory molecules are able to compensate for the loss of CD80 and CD86 to boost the activation of T cells in response to LCMV, but not the herpes-like virus. Further experiments showed that LCMV triggers a lot more inflammation in infected cells than the other virus. This leads to the production of many different types of co-stimulatory molecules, which ensures that if one fails to boost the activation of CD8 ⁺ T cells, another molecule can do so instead. Better understanding of how these co-stimulatory molecules work could help scientists to develop more effective vaccines in future.

DOI: http://dx.doi.org/10.7554/eLife.07486.002