The Costimulatory Molecule CD27 Maintains Clonally Diverse CD8+ T Cell Responses of Low Antigen Affinity to Protect against Viral Variants

Abstract

CD70 and CD27 are costimulatory molecules that provide essential signals for the expansion and differentiation of CD8(+) T cells. Here, we show that CD27-driven costimulation lowered the threshold of T cell receptor activation on CD8(+) T cells and enabled responses against low-affinity antigens. Using influenza infection to study in vivo consequences, we found that CD27-driven costimulation promoted a CD8(+) T cell response of overall low affinity. These qualitative effects of CD27 on T cell responses were maintained into the memory phase. On a clonal level, CD27-driven costimulation established a higher degree of variety in memory CD8(+) T cells. The benefit became apparent when mice were reinfected, given that CD27 improved CD8(+) T cell responses against reinfection with viral variants, but not with identical virus. We propose that CD27-driven costimulation is a strategy to generate memory clones that have potential reactivity to a wide array of mutable pathogens.

IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization

“…This failure to recapitulate the magnitude of the T-cell response to Poly I:C/αCD40 indicates that IL-27 cannot completely replicate the complex inflammatory environment instigated by the TLR agonist. We and others previously published on an important role for CD70-CD27 interactions in the T-cell response to combined TLR/ CD40 immunization (24,25,54) as well as to infectious challenge/ vaccination (55)(56)(57)(58). Because IL-27 and CD27 separately are required for maximal T-cell responses after subunit vaccination, neither alone is therefore sufficient for maximal T-cell expansion.…”

CD70-Driven Costimulation Induces Survival or Fas-Mediated Apoptosis of T Cells Depending on Antigenic Load

“…The crucial role of CD70-driven costimulation becomes evident postinfection with acute viruses such as vaccinia virus, vesicular stomatitis virus, and the A/NT/60/68 strain of the influenza virus, during which CD70 and CD27 essentially contribute to the size of the CD8 T cell response (14,21). Recently, we found that CD27 does not have an apparent role in the regulation of the size of primary CD8 T cell responses postinfection with other strains of influenza (22). Close inspection revealed that CD27 favors the outgrowth of low-affinity CD8 T cells at the cost of high-affinity CD8 T cells, suggesting that the costimulatory effects of CD27 depend on the affinity of the Ag interactions (22).…”

“…Recently, we found that CD27 does not have an apparent role in the regulation of the size of primary CD8 T cell responses postinfection with other strains of influenza (22). Close inspection revealed that CD27 favors the outgrowth of low-affinity CD8 T cells at the cost of high-affinity CD8 T cells, suggesting that the costimulatory effects of CD27 depend on the affinity of the Ag interactions (22). In fact, CD27 enhances the cell death of CD8 T cells stimulated with high-affinity Ags, whereas CD27 improves T cell survival after stimulation with similar amounts of low-affinity Ags (22).…”

“…Close inspection revealed that CD27 favors the outgrowth of low-affinity CD8 T cells at the cost of high-affinity CD8 T cells, suggesting that the costimulatory effects of CD27 depend on the affinity of the Ag interactions (22). In fact, CD27 enhances the cell death of CD8 T cells stimulated with high-affinity Ags, whereas CD27 improves T cell survival after stimulation with similar amounts of low-affinity Ags (22). A reverse role for CD27 signaling in effector CD8 T cell differentiation is supported by the CD27-driven reduction rather than enhancement of CD8 T cell responses after chronic infection with lymphocytic choriomeningitis virus (LCMV) (23,24).…”

CD27 costimulation contributes substantially to the expansion of functional memory CD8+T cells after peptide immunization

“…However, whether CD27 similarly plays a role during memory T-cell activation has been less clear; many studies that sought to address this question have made use of CD27-deficient or CD70-overexpressing mice in which interpretation of the memory CD8 + T-cell response is complicated by the impact of CD27/CD70 signals on CD8 + T-cell priming/imprinting and memory differentiation [6,9,12,41,42]. Furthermore, the remaining studies have reported conflicting results.…”