Abstract
T cells are critical for a functioning adaptive immune response and a strong correlation exists between T cell responses and T cell receptor (TCR): peptide-loaded MHC (pMHC) binding. Studies that utilize pMHC tetramer, multimers, and assays of three-dimensional (3D) affinity have provided advancements in our understanding of T cell responses across different diseases. However, these technologies focus on higher affinity and avidity T cells while missing the lower affinity responders. Lower affinity TCRs in expanded polyclonal populations almost always constitute a significant proportion of the response with cells mediating different effector functions associated with variation in the proportion of high and low affinity T cells. Since lower affinity T cells expand and are functional, a fully inclusive view of T cell responses is required to accurately interpret the role of affinity for adaptive T cell immunity. For example, low affinity T cells are capable of inducing autoimmune disease and T cells with an intermediate affinity have been shown to exhibit an optimal anti-tumor response. Here, we focus on how affinity of the TCR may relate to T cell phenotype and provide examples where 2D affinity influences functional outcomes.
Highlights
Recognition of peptide-loaded MHC (pMHC) by T cell receptor (TCR) is the initial trigger for activation of T cells and provides a gateway to the adaptive immune response
Beneath this surface a detector records the change of resonance angle, giving a read out of affinity as the number of molecules per volume, μM−1. (c) 2D affinity measurements by 2D micropipette adhesion frequency assay (2D-MP) show the interaction of TCR embedded in live T cells interacting with pMHC bound to surrogate antigen presenting cell (APC)’s in
Beneath this surface a detector records the change of resonance angle, giving a read out of affinity as the number of molecules per volume, μM−1 . (c) 2D affinity measurements by 2D-MP show the interaction of TCR embedded in live T cells interacting with pMHC bound to surrogate APC’s in the form of red blood cells (RBCs), these two cells are mechanically brought into contact and adhesion frequency is measured
Summary
Recognition of pMHC by TCR is the initial trigger for activation of T cells and provides a gateway to the adaptive immune response. The affinity of TCR:pMHC interactions is an important initial regulatory parameter in activation. T cells responding to as few as 1–10 pMHCs on an antigen presenting cell [7,8,9] This interaction is decidedly specific [10] with the ability to differentiate single amino acid substitutions in peptide sequences that are translated into differential phenotypic responses [11]. This sensitivity, specificity, and the extent to which a naïve T cell receives stimulation via the TCR contributes to the activation status and phenotype of that cell. We discuss the emerging body of work illustrating the significance of TCR two-dimensional affinity for pMHC (which is not to be confused with TCR avidity for pMHC) in the initiation and dissemination of T cell signaling during attack of invading pathogens and autoimmune conditions
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