Functional Avidity: A Measure to Predict the Efficacy of Effector T Cells?

Abstract

The functional avidity is determined by exposing T-cell populations in vitro to different amounts of cognate antigen. T-cells with high functional avidity respond to low antigen doses. This in vitro measure is thought to correlate well with the in vivo effector capacity of T-cells. We here present the multifaceted factors determining and influencing the functional avidity of T-cells. We outline how changes in the functional avidity can occur over the course of an infection. This process, known as avidity maturation, can occur despite the fact that T-cells express a fixed TCR. Furthermore, examples are provided illustrating the importance of generating T-cell populations that exhibit a high functional avidity when responding to an infection or tumors. Furthermore, we discuss whether criteria based on which we evaluate an effective T-cell response to acute infections can also be applied to chronic infections such as HIV. Finally, we also focus on observations that high-avidity T-cells show higher signs of exhaustion and facilitate the emergence of virus escape variants. The review summarizes our current understanding of how this may occur as well as how T-cells of different functional avidity contribute to antiviral and anti-tumor immunity. Enhancing our knowledge in this field is relevant for tumor immunotherapy and vaccines design.

T-helper cell receptors from long-term survivors after telomerase cancer vaccination for use in adoptive cell therapy

“…The latter finding is consistent with the notion that high-avidity T cells may be susceptible to exhaustion and activation-induced cell death, as has been reported from studies in chronic infections. 47 In the cancer setting, however, the tumor antigen load may not be high enough to trigger this mechanism. In unpublished experiments, we have observed that some high-avidity clones alter their cytokine profile when stimulated with high antigen concentrations.…”

“…It is not known whether this would be an issue in the cancer setting. Most investigators consider that high-affinity TCRs are desirable for cancer eradication, [47][48][49] whereas others have raised concerns regarding autoimmune side effects and also suggested that there is an affinity plateau which should not be exceeded. 41,50 We aim to use our comprehensive biobank of hTERT-reactive clones to develop a panel of TCRs with different affinities and assess their survival and functionality after infusion into patients.…”

TCR-ligand dissociation rate is a robust and stable biomarker of CD8+ T cell potency

“…Protective immunity against intracellular pathogens relies on the individual CD8 + T cell capacity to display multiple effector functions or polyfunctionality (10). We hypothesized that the kinetics of TCR-pMHC interactions could also affect their polyfunctionality.…”

“…Yet, others have challenged the functional superiority of such high-avidity cells, which may be prone to increased activation-induced cell death, senescence, or exhaustion (reviewed in ref. 10). In the context of antitumor responses, results obtained from melanoma patients also indicate that T cells of high functional avidities are required for efficient protection (11)(12)(13).…”

Low Antigen Dose in Adjuvant-Based Vaccination Selectively Induces CD4 T Cells with Enhanced Functional Avidity and Protective Efficacy

“…The strength of binding between a T cell and the APC is crucial and is highly dependent on TCR affinity and structural avidity for the cognate MHC-peptide complex on the APC (10). However, the strength of the immunological synapse and functional avidity between a T cell and the APC are also affected by TCR-coreceptor expression, costimulatory receptor expression levels on T cell/APC, localization of TCR in lipid rafts, TCR signaling efficiency, and the local cytokine/inflammatory milieu among others (11,12). Despite this complexity, readouts for functional avidity are rather straightforward; they measure the Ag concentration required to activate T cells as assessed by functional assays, including cytokine production, proliferation, and target cell lysis.…”