T-cell avidity and tuning: the flexible connection between tolerance and autoimmunity

Abstract

Thymic T-cell selection mechanisms generate a cross-reactive, self-MHC restricted peripheral T-cell pool. Affinity and avidity are of profound influence on this selection and the generation of immunity. Autoreactive T cells can escape thymic deletion by lowering their avidity and retain this "tuned" state in the periphery. Upon activation, tuned T cells can cause autoimmunity, while immunotherapeutic strategies may be hampered by existing T-cell tolerance. The regulation of T-cell avidity and tuning therefore determines the balance between tolerance and autoimmunity and should be taken into account in the design of therapeutic strategies aimed at T-cell reactivity.

FIGURE 1

Several factors influence structural T-cell avidity: (A) Expression levels of TCR and MHC molecules, affinity of the peptide for the MHC molecule, and the affinity of the TCR for the peptide-MHC complex are basic factors of structural T-cell avidity. Furthermore, different coreceptor subtypes (such as CD8-αα or -αβ) display different affinities for the TCR complex, additionally influencing antigen recognition efficiency. (B) Besides availability of the MHC and TCR complexes, the expression levels of different co-stimulatory and adhesion molecules on the surface of the APC and T cell, and their ability to interact, are important determinants for proper activation and prolonged cell-cell contact. (C) Recognition of the peptide-MHC complex by the TCR, combined with co-stimulatory signaling and adhesion-molecule interaction, will induce a transient stop signal for the migrating T cell. This allows for prolonged TCR signaling and the assembly of an immunological synapse (IS), and eventually the formation of a supramolecular activation cluster (SMAC). Subsequent biological function depends on the T cell’s functional avidity, determined by the regulation of activation thresholds and induction of different signaling cascades.

FIGURE 2

Schematic representation of the signaling pathways involved in T-cell activation. Antigen recognition by the TCR and coreceptor (CD4 or CD8) ligation releases Lck from Csk inhibition, leading to phosphorylation of the TCR ξ-chains and recruitment of ZAP-70. ZAP-70 phosphorylates LAT, which ligates PLCγ-1 and thereby amplifies and sustains the activation signal. PLCγ-1 can activate different signaling cascades via cleavage of PIP2, such as the PKC and calcineurin pathways leading to cellular activation and differentiation. The function of PLCγ-1 is further enhanced by CD28 ligation, via interaction with Ltk. Additionally, LAT can interact with several linker molecules, leading to activation of the MAPK-pathway via activation of Ras or the Rho A pathway leading to actin reorganization.