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.

CD4+ T Cell Help Selectively Enhances High-Avidity Tumor Antigen-Specific CD8+ T Cells

“…Although our study demonstrates that provision of CD4 help preferentially augmented TCR hi T cells both in vitro and in vivo, Sherman and colleagues (14,32) reported that tumor Ag-specific CD4 + T help increased expansion as well as effector functions of both high-and low-avidity tumor Ag-specific CD8 + T cells, which resulted in tumor eradication. In those studies, both CD4 + and CD8 + T cells recognized a surrogate tumor Ag that was expressed as a transgene by an autochthonous tumor.…”

Quantitative TCR:pMHC Dissociation Rate Assessment by NTAmers Reveals Antimelanoma T Cell Repertoires Enriched for High Functional Competence

“…Reports have shown that stronger TCR:pMHC interactions generate superior effector functions in mice (19,(33)(34)(35) and humans (36)(37)(38). However, the impact of TCR/CD8:pMHC avidity on CD8 T cell differentiation and clonotype repertoire selection within the periphery remains poorly understood.…”

Boost and loss of immune responses against tumor-associated antigens in the course of pregnancy as a model for allogeneic immunotherapy

“…42 These low-and high-avidity immune cells have the capacity to expand and exert killing functions on leukemic cells as shown in vitro and in animal models postvaccination. 12,54,55 The exploitation of donor-derived autoimmunity against selected TAAs by improving donor selection and facilitating adoptive immunotransfer of donor-derived T lymphocytes may significantly contribute to the control of the malignant disease in the absence of GVHD after allotransplantation, where an optimal environment offers unique opportunities for homeostatic expansion. 11,56 The presence of the target antigen represents an essential condition for the persistence of the TAA-specific immune responses, as suggested by the studies in the course of pregnancy.…”