Signaling Mechanisms that Balance Anti-viral, Auto-reactive, and Antitumor Potential of Low Affinity T Cells

Abstract

For T cell activation, three signals have to be provided from the antigen presenting cell; Signal 1 (antigen recognition), signal 2 (co-stimulation) and signal 3 (cytokine priming). Blocking negative co-stimulation during antigen presentation to T cells is becoming a promising therapeutic strategy to enhance cancer immunotherapy. Here we will focus on interference with PD-1/PD-L1 negative co-stimulation during antigen presentation to T cells as a therapeutic approach. We will discuss the potential mechanisms and the therapeutic consequences by which interference/inhibition with this interaction results in anti-tumour immunity. Particularly, we will comment on whether blocking negative co-stimulation provides differentiation signals to T cells undergoing antigen presentation. A major dogma in immunology states that T cell differentiation signals are given by cytokines and chemokines (signal 3) rather than co-stimulation (signal 2). We will discuss whether this is the case when blocking PD-L1/PD-1 negative co-stimulation.

A Mathematical Model of Immune Activation with a Unified Self-Nonself Concept

“…The condition (3) imposes a quality constraint on activated T cell clones to enter a highly proliferative state and implies that among T cell clones that are in the activated state, only the T cell clones with a sufficiently high proliferation rate ( a ) or IL-2 secretion rate ( d ) are able to contribute to the immune response against Ag. Since both, the proliferation and IL-2 secretion rate of activated T cells depend on the affinity/avidity of their TCR to the presented Ag ( 32 – 34 ), condition (3) implies that the existence of T cell clones with sufficiently high specificity for the presented Ag is required for induction of an immune response. Similar implications were derived from a model that considers a nonlinear IL-2 dependent proliferation rate of activated T cells (Nonlinear Proliferation Rate of Conventional and Regulatory T Cells in Appendix).…”

“…The major focus of central tolerance is to eliminate T cells that are self-specific. Therefore, it is unlikely that highly self-specific T cells escape from central tolerance, as they are more effectively detected and eliminated in the thymus ( 12 , 34 ). It is thus expected that autoreactive T cells in the periphery are less aggressive than the ones that undergo clonal deletion in the thymus, and may not fulfill condition (3).…”

“…Although the activation of autoreactive T cells has been shown to be involved in autoimmunity ( 12 ), several lines of evidences indicate that these cells are required for limiting self-destruction by supporting self-regenerative processes ( 54 – 56 ). In addition, the anti-tumor immune responses evoked by autoreactive T cells are beneficial ( 34 , 57 ). Therefore, it seems unlikely that autoreactive T cells escaping from the thymus are simply a result of thymic selection error that can disturb self-tolerance under certain physiological conditions.…”