T Cell Resistance: On the Mechanisms of T Cell Non-activation

Abstract

Immunological tolerance is a fundamental arm of any functioning immune system. Not only does tolerance mitigate collateral damage from host immune responses, but in doing so permits a robust response sufficient to clear infection as necessary. Yet, despite occupying such a cornerstone, research aiming to unravel the intricacies of tolerance induction is mired by interchangeable and often misused terminologies, with markers and mechanistic pathways that beg the question of redundancy. In this review we aim to define these boarders by providing new perspectives to long-standing theories of tolerance. Given the central role of T cells in enforcing immune cascades, in this review we choose to explore immunological tolerance through the perspective of T cell 'resistance to activation,' to delineate the contexts in which one tolerance mechanism has evolved over the other. By clarifying the important biological markers and cellular players underpinning T cell resistance to activation, we aim to encourage more purposeful and directed research into tolerance and, more-over, potential therapeutic strategies in autoimmune diseases and cancer. The tolerance field is in much need of reclassification and consideration, and in this review, we hope to open that conversation.

Keywords: Clonal Anergy; Immune Tolerance; Immunotherapy; Senescence; T cells; T-Cell Exhaustion.

Figure 1. When a T cell (orange) contacts an APC (purple) or target cell, the contact progresses from an early kinapse to a stable immunological synapse. During this contact, distinct types of internal and external signals are integrated to coordinate the process of T cell activation and subsequent differentiation. When a specific antigen is recognized by the TCR S1), the activation is initiated and signalling microclusters, containing the TCR and other co-activator molecules (S2), are immediately formed. The architecture of a multifocal synapse (shown here) is less well characterised than a monofocal synapse wherein microclusters migrate to the centre of the contact. The cytokine milieu (S3) during and after the contact will affect the differentiation of the T cell into effector or memory cell, for example. Release of synaptic vesicles will follow (S4) to mediate the horizontal transfer of biological material between the two cells involved.

S1, signal 1; S2, signal 2; S3, signal 3; S4, signal 4.

Figure 2. Cartoon representing the cell cycle phases and a T cell (orange) exiting quiescence after being activated by an effective contact with an APC (purple). T cells will enter the cell cycle each time they recognize an antigen in order to expand and respond. T cells of old individuals will, after multiple rounds of cell-cycle entry, naturally enter a permanent state of senescence that will impair their activation potential. Shortening of telomeres has been suggested to drive senescence. APCs can transfer telomeres within vesicles across the immunological synapse to rescue a T cell from senescence.

Figure 3. Cartoon representing the molecular mechanisms involved in exhaustion of T cells after repeated exposure to an antigen. In the context of antigen persistence, several co-inhibitory receptors, like PD-1 or CTLA4, counteract TCR signalling pathways. Other mechanisms driving T cell exhaustion involve the cytokine milieu. For example, while IL-2 can potentiate TCR signalling to reverse exhaustion, IL-10 impairs it. Exhaustion is also intimately linked to the metabolic state of the T cell. Hypoxia or low glucose availability, usually related to the tumour microenvironment, can dramatically impair mitochondrial function and therefore, T cell activation.