title: Functional differences between low- and high-affinity CD8(+) T cells in the tumor environment.
abstract: Weak T-cell antigen receptor (TCR)-ligand interactions are sufficient to activate naïve CD8(+) T cells, but generally do not result in tumor eradication. How differences in TCR affinity affect the regulation of T-cell function in an immunosuppressive tumor environment has not been investigated. We have examined the functional differences of high- vs. low-affinity CD8(+) T cells and we observed that infiltration, accumulation, survival and cytotoxicity within the tumor are severely impacted by the strength of TCR-ligand interactions. In addition, high-affinity CD8(+) T cells were found to exhibit lower expression of inhibitory molecules including PD-1, LAG-3 and NKG2A, thus being less susceptible to suppressive mechanisms. Interferon γ and autocrine interleukin-2 were both found to influence the level of expression of these molecules. Interestingly, although high-affinity CD8(+) T cells were superior to low-affinity CD8(+) T cells in their ability to effect tumor eradication, they could be further improved by the presence of tumor specific CD4(+) T cells. These findings illustrate the importance of both TCR affinity and tumor-specific CD4 help in tumor immunotherapy.
authors.affiliation: Department of Immunology and Microbial Sciences; The Scripps Research Institute; La Jolla, CA USA.
authors.forename: Rinke
authors.initials: R
authors.lastname: Bos
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Marquardt
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Cheung
authors.forename: Linda A
authors.initials: LA
authors.lastname: Sherman