Not-so-opposite ends of the spectrum: CD8+ T cell dysfunction across chronic infection, cancer and autoimmunity

Abstract

CD8⁺ T cells are critical mediators of cytotoxic effector function in infection, cancer and autoimmunity. In cancer and chronic viral infection, CD8⁺ T cells undergo a progressive loss of cytokine production and cytotoxicity, a state termed T cell exhaustion. In autoimmunity, autoreactive CD8⁺ T cells retain the capacity to effectively mediate the destruction of host tissues. Although the clinical outcome differs in each context, CD8⁺ T cells are chronically exposed to antigen in all three. These chronically stimulated CD8⁺ T cells share some common phenotypic features, as well as transcriptional and epigenetic programming, across disease contexts. A better understanding of these CD8⁺ T cell states may reveal novel strategies to augment clearance of chronic viral infection and cancer and to mitigate self-reactivity leading to tissue damage in autoimmunity.

Figure 1:. “Opposite ends of the spectrum” framework of CD8+ T cells in autoimmunity versus chronic viral infection.

CD8+ T cells in autoimmunity (left) exhibit excessive and inappropriate effector functionality. In some autoimmune diseases, CD8+ T cells cause extensive damage of self-tissue by overcoming numerous tolerance mechanisms that normally prevent and/or halt this reaction in homeostasis. In contrast, CD8+ T cells in chronic viral infection and cancer (right) become “exhausted” and exhibit reduced effector functionality, as compared to effector function elicited by acute infection. This dysfunction contributes to viral persistence and continued tumor growth. Blockade of immune checkpoints such as co-inhibitory receptors PD-1 and CTLA-4 can augment effector functionality of CD8+ T cells in both contexts, leading to better control of chronic viral infection/cancer and exacerbated autoimmunity.

Figure 2:. Temporal changes of CD8+ T cells in cancer, chronic viral infection, and autoimmunity.

Antigen-specific CD8+ T cells progressively develop distinct phenotypic changes in the context of chronic stimulation in disease. The phenotypic changes described for bulk autoreactive CD8+ T cells are generalized from various studies of diabetogenic and encephalitogenic T cells within the affected organ of mouse models. The changes in T cell properties are described as disease progresses from an early to late time point, corresponding to approximately: day 7 and day 30–60 of LCMV Clone 13 infection; TILs in newly developing tumors compared to TILs in late-stage tumors; early NOD insulitis at 3–4 weeks of age to overt diabetes at 10–12 weeks; and early day 7 of CNS autoimmunity in MOG-GP mice compared to day 28. Changes are described for cancer (purple), chronic viral infection (orange), and autoimmunity (cyan).