Immunogenic and tolerogenic cell death

Abstract

The immune system is routinely exposed to dead cells during normal cell turnover, injury and infection. Mechanisms must exist to discriminate between different forms of cell death to correctly eliminate pathogens and promote healing while avoiding responses to self, which can result in autoimmunity. However, an effective immune response against host tissue is often needed to eliminate tumours following treatment with chemotherapeutic agents that trigger tumour cell death. Consequently, a central problem in immunology is to understand how the immune system determines whether cell death is immunogenic, tolerogenic or 'silent'.

Figure 1. Characteristics of immunogenic cell death

When cells succumb to the immunogenic variant of apoptosis, they expose calreticulin (CRT) on the cell surface at a pre-apoptotic state. Moreover, they may expose other chaperones including members of the heat shock protein (HSP) family. Later, they release the DAMP HMGB1 as well as other, yet-to-be-characterized factors. The surface-exposed molecules as well as soluble products from dying cells affect the function of DC through the action on specific receptors. For details see main text.

Figure 2. Mechanisms of tolerance induction by apoptotic cells

Apoptotic cells either do not release DAMPs or modify them (e.g., HMGB1, see text) and are engulfed by DC. TGFβ, produced by the dying cells or the engulfing cells induce the differentiation of inducible Treg, which inhibit immune responses. Alternatively, CD8⁺ T cells are stimulated in the absence of activated CD4⁺ T cells, resulting in helpless CTL. These are capable of a primary cytotoxic response, but upon restimulation produce TRAIL. As a result, they themselves die while also inhibiting new immune responses, resulting in tolerance.

Figure 2. Mechanisms of tolerance induction by apoptotic cells

Apoptotic cells either do not release DAMPs or modify them (e.g., HMGB1, see text) and are engulfed by DC. TGFβ, produced by the dying cells or the engulfing cells induce the differentiation of inducible Treg, which inhibit immune responses. Alternatively, CD8⁺ T cells are stimulated in the absence of activated CD4⁺ T cells, resulting in helpless CTL. These are capable of a primary cytotoxic response, but upon restimulation produce TRAIL. As a result, they themselves die while also inhibiting new immune responses, resulting in tolerance.