Signaling through the T-cell receptor (TCR) drives multiple downstream processes, including T-cell activation, differentiation, proliferation, and release of effector cytokines and chemokines. In turn, this process upregulates the expression of inhibitory immune checkpoint receptors such as PD-1, CTLA-4, or LAG-3, which oppose signals through costimulatory receptors and serve as critical rheostats to abrogate or temper TCR signaling. These receptors play critical roles to shut down effector T-cell responses to limit immunopathology during infection or tissue inflammation, thereby maintaining homeostasis and preserving tissue integrity. Importantly, although these checkpoint receptors are expressed on both CD4+ and CD8+ T cells, among other immune cells, some of their ligands may be expressed on both hematopoietic and nonhematopoietic cells, as well as tumor cells (Table 1). Notably, ligands such as PD-L1 may be upregulated within the tumor microenvironment on tumor cells and hematopoietic cells [1]. Thus, these immune checkpoint receptors regulate responses in lymphoid tissues (e.g. spleen and lymph nodes), peripheral tissues, and the tumor microenvironment.

Over the past decade, blockade of these inhibitory immune checkpoint receptors has been used to augment antitumor T-cell effector functions and has revolutionized cancer care. In contrast, in both human autoimmune diseases and experimental mouse models of autoimmunity, where pathologic effector cells functionally surpass suppression by regulatory cells, the functions of immune checkpoint receptors are impaired, underscoring their importance in tolerance. Genetic studies have revealed the important roles of checkpoint inhibitors in both the induction and maintenance of peripheral T-cell tolerance. For example, genetic deletion of programmed cell death protein 1 (Pdcd1) (encoding PD-1) or Lag3 accelerated type-1 diabetes (T1D) in the nonobese diabetic (NOD) mouse model 2, 3. Likewise, loss-of-function mutations in either CTLA4 or Lipopolysaccharide-responsive and beige-like anchor protein (LRBA), which alters trafficking of CTLA-4 to the cell membrane, lead to human autoimmune syndromes with parallels to the Ctla4 knockout mouse model [4]. Similarly, polymorphisms in CTLA4 or PDCD1 are associated with the development of multiple autoimmune diseases 5, 6. Moreover, immune checkpoint receptors can exert differing effects on pathogenic effector cells or regulatory T cells 7, 8, 9, revealing further ways these receptors control T-cell tolerance and autoimmunity. To this end, a recent study of single-cell expression quantitative trait loci demonstrated the effects of genetic variants of CTLA4 and PDCD1 on their transcriptional expression in different CD4+ T-cell types [10].

In this review, we focus on recent advances in understanding immune checkpoint receptors on effector cells in the context of autoimmunity. We first discuss the discovery of gene programs that coordinate expression of checkpoint receptors. Next, we highlight recent work identifying autoreactive T cells with features of T-cell exhaustion and anatomic locations of reservoirs of autoreactive T cells. We then discuss parallels between immune checkpoint blockade-induced immune-related adverse events (irAE) and autoimmunity. Finally, we summarize recent studies on bidirectional functional interactions between immune checkpoint receptors and their ligands, and the implications of these interactions for tolerance and autoimmunity.