Strength and Numbers: The Role of Affinity and Avidity in the 'Quality' of T Cell Tolerance

Abstract

The ability of T cells to identify foreign antigens and mount an efficient immune response while limiting activation upon recognition of self and self-associated peptides is critical. Multiple tolerance mechanisms work in concert to prevent the generation and activation of self-reactive T cells. T cell tolerance is tightly regulated, as defects in these processes can lead to devastating disease; a wide variety of autoimmune diseases and, more recently, adverse immune-related events associated with checkpoint blockade immunotherapy have been linked to a breakdown in T cell tolerance. The quantity and quality of antigen receptor signaling depend on a variety of parameters that include T cell receptor affinity and avidity for peptide. Autoreactive T cell fate choices (e.g., deletion, anergy, regulatory T cell development) are highly dependent on the strength of T cell receptor interactions with self-peptide. However, less is known about how differences in the strength of T cell receptor signaling during differentiation influences the 'function' and persistence of anergic and regulatory T cell populations. Here, we review the literature on this subject and discuss the clinical implications of how T cell receptor signal strength influences the 'quality' of anergic and regulatory T cell populations.

Keywords: T cell receptor signaling; T cells; affinity; anergy; avidity; heterogeneity; immunotherapy; regulatory T cells (Treg); tolerance.

Figure 2

T cell receptor signal strength influences the ‘quality’ of Treg and anergic cells. (Top panel) During T cell development, αβ-lineage thymocytes test the reactivity of their T cell receptor (TCR) to self-peptides. The fate of the developing T cell is dependent on the strength of this interaction. T cells experiencing very low and very high functional avidity to self-peptides are deleted by neglect or clonal deletion, respectively. Low to moderate affinity interactions support the development of conventional CD4⁺ and CD8⁺ T cells. Moderate to high affinity interactions drive regulatory T cell (natural Treg) generation; the strength of these interactions overlap with MHC class II-restricted TCR signals that support both positive and negative selection [69] and are likely influenced by environmental cues that determine cell fate choice in this range of avidity [70]. (Middle and bottom panels) Influence of TCR signals on nTreg function as well as CD4⁺ and CD8⁺ T cell anergy induction and peripheral Treg (pTreg) differentiation.

Figure 1

Factors that influence the affinity, avidity, and functional avidity of T cells. T cell receptor (TCR) affinity is defined by the strength of an interaction between a single TCR and a given peptide presented by a major histocompatibility complex (MHC) molecule. It depends on the amino acid sequence of the TCR, the sequence of the peptide being presented, and the MHC allele. TCR avidity is dependent on both the affinity of a single TCR molecule for a given pMHC and the number of TCR-pMHC engagements. Functional avidity, also known as antigen sensitivity, considers also the influence of co-receptors, co-signaling molecules, adhesion molecules, and cytokines that might influence the overall intensity and duration of the TCR signal. Multiple approaches (in brackets) can be used to manipulate the different parameters to influence TCR signal strength.