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Published in final edited form as: Curr Opin Immunol. 2023 Jan 28;80:102283. doi: 10.1016/j.coi.2023.102283

Immune Checkpoint Receptors in Autoimmunity

Kelly P Burke 1,2, Dillon G Patterson 2, Dan Liang 2, Arlene H Sharpe 2,3,4,*
PMCID: PMC10019320  NIHMSID: NIHMS1864696  PMID: 36709596

Abstract

Immune checkpoint receptors such as PD-1, CTLA-4, LAG3, and TIGIT have distinct and overlapping inhibitory functions that regulate T cell activation, differentiation, and function. These inhibitory receptors also mediate tolerance, and dysregulation of these receptors can result in a breach of tolerance and the development of autoimmune syndromes. Similarly, antibody blockade of immune checkpoint receptors or their ligands for cancer immunotherapy may trigger a spectrum of organ inflammation that resembles autoimmunity, termed immune-related adverse events (irAE). In this review, we discuss recent advances in the regulation of autoimmunity by immune checkpoint receptors. We highlight coordinated gene expression programs linking checkpoint receptors, heterogeneity within autoreactive T cell populations, parallels between irAE and autoimmunity, and bidirectional functional interactions between immune checkpoint receptors and their ligands.

Introduction

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 LAG3, which oppose signals through costimulatory receptors and serve as critical rheostats to abrogate or temper TCR signaling. These receptors play critical roles to shutdown 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 non-hematopoietic 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.

Table 1:

Selected immune checkpoint receptors, their cell-type-specific expression patterns, and ligands in non-tumor tissue.

Immune checkpoint receptor (Alternate name, Gene name) Cell types expressing receptor Immune checkpoint ligand (Gene name) Cell types expressing ligand Ref
PD-1 (Pdcd1) CD279 T cells
B cells
NK cells
Myeloid		 PD-L1 (B7-H1; CD274) Hematopoietic (antigenpresenting cells, T cells, B cells)
Non-hematopoietic (e.g., vascular endothelial cells, pancreatic islets, liver non-parenchymal cells, placental syncytiotrophoblasts)		 [1]
PD-L2 (B7-DC; CD273) Hematopoietic (dendritic cells, macrophages, some B cells, some mast cells, Th2 CD4+ cells); non-hematopoietic (lung epithelial cells)
CTLA-4 (Ctla4) CD152 T cells
B1a cells		 B7–1 (Cd80) Hematopoietic (antigen presenting cells) [47,48]
B7–2 (Cd86)
LAG3 (Lag3) CD223 T cells
NK cells
NKT
B cells		 MHC-II Hematopoietic (antigenpresenting cells, T cells, B cells, macrophages) [49,50]
Galectin-3 Non-hematopoietic tissues (e.g., epithelial cells, endothelial cells)
LSECtin Liver
FGL-1 Liver
TIGIT (Tigit) WUCAM,
VSIG9,
VSTM3		 T cells
NK cells
Gamma-delta T cells		 CD115 (Pvr) Hematopoietic (antigenpresenting cells, T cells, B cells, macrophages) Non-hematopoietic cells [49,51]
CD112 (PVRL2; Nectin-2)
CD113 (PVRL3; Nectin-3) Non-hematopoietic cells
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Over the past decade, blockade of these inhibitory immune checkpoint receptors has been used to augment anti-tumor 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 Pdcd1 (encoding PD-1) or Lag3 accelerated type 1 diabetes (T1D) in the non-obese diabetic (NOD) mouse model [2,3]. Likewise, loss-of-function mutations in either CTLA4 or LRBA, which alters trafficking of CTLA-4 to the cell membrane, leads 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 [7–9], revealing further ways these receptors control T cell tolerance and autoimmunity. To this end, a recent study of single-cell expression quantitative trait loci (sc-eQTL) 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 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.

Coordinated expression of checkpoint receptors on T cells

Loss of a single checkpoint receptor has been associated with compensatory upregulation of other inhibitory molecules in models of chronic viral infection, tumor and autoimmunity [7,8,11,12], suggesting an underlying shared regulation of checkpoint receptors. Using a murine tumor model, Chihara et al. identified a shared gene regulatory program of costimulatory and coinhibitory checkpoint molecules (including Ctla4, Lag3, Havcr2 (encoding TIM-3), Icos) across multiple states of T cell hyporesponsiveness, including autoimmunity, that was driven by IL-27 signaling [13]. Intriguingly, although Pdcd1 was identified as part of this gene program transcriptionally, its protein expression was not affected by loss of IL-27, highlighting potential regulatory differences among checkpoint receptors. As IL-27 is at least partially regulated by IFN-β, Sumida et al. assessed the effects of both IL-27 and IFN-β on induction of coinhibitory receptor expression in human T cells [14]. In both in vitro experiments and within an in vivo dataset, IFN-β induced expression of PD-1, TIM-3, and LAG3 but inhibited expression of TIGIT, with these effects driven by different interferon-specific gene modules [14]. These types of systems biology approaches have the ability to highlight regulatory mechanisms shared across diseases and identify novel therapeutic targets.

Heterogeneity of autoreactive CD8+ T cells at sites of inflammation

In the periphery, autoreactive T cells may be presented with self-antigen and continuously stimulated. Persistent stimulation with self-antigen has similarities with chronic viral infection, where continuous T cell receptor signaling leads to a dysfunctional CD8+ T cell program, known as T cell exhaustion. T cell exhaustion is characterized by transcriptional and epigenetic changes leading to elevated expression of inhibitory receptors, and loss of proliferative capacity, cytokine production, and cytotoxicity [15–17]. Substantial heterogeneity exists among exhausted CD8+ T cells, including a self-renewing stem-like population that give rise to terminally differentiated subsets expressing high levels of the co-inhibitory molecules PD-1, TIM-3, and LAG3, among others [18–21].

Intriguingly, a subset of pathogenic T cells expressing hallmarks of terminally exhausted T cells (PD-1, LAG3, TOX) and a self-renewing stem-like population (TCF1) have recently been described in multiple autoimmune models, including a model of chronic CNS inflammation [22] and T1D in NOD mice [23,24]. In a model of chronic CNS inflammation, the transcription factor TOX was dispensable for the initial expansion of autoreactive CD8+ T cells but required for their persistence in the tissue. Notably, the presence of TOX was required for the expression of PD-1, TIGIT, and LAG3, suggesting a role for TOX in controlling autoreactive CD8+ T cell differentiation and survival [22]. Likewise, a subset of infiltrating CD8+ T cell population in pancreatic islets at the time of diabetes expressed PD-1, TOX, TIGIT, and LAG3 [24]. Within this exhausted-like subset, LAG3 restricted progression of diabetes, in part by limiting proliferation and effector function [24]. Together, these studies suggest the presence of immune checkpoint molecules may promote the long-term survival and tissue adaptation of autoreactive T cells. Further studies are needed to define how autoreactive cells with features of T cell exhaustion arise relative to the more numerous autoreactive pathogenic cells. Importantly, these disease models show significant differences in patterns of checkpoint receptor expression and T cell functionality, including cytokine production, compared to exhausted T cells in chronic viral infection or malignancy. The differences between chronic infection and cancer versus autoimmunity suggest a nuanced context-specific role for each checkpoint receptor in regulating T cell activation, differentiation, and trafficking to target organs following chronic stimulation.

The reservoir of autoreactive T cells

Two recent studies identified a reservoir of stem-like autoreactive T cells that are maintained outside the site of organ inflammation. Transcriptional profiling of antigen-specific autoreactive CD8+ T cells from pancreatic LN (pLN) and pancreas of mice with T1D identified a transition from stem-like TCF1hi “autoimmune progenitors” in pLN to TCF1lo “autoimmune mediators” in pLN and pancreas [25], pointing to a progenitor pool within the pLN. Likewise, paired scRNA-/TCR-seq of Th17 cells from the CNS, peripheral lymphoid organs, and intestinal tissues from EAE mice found a TCF1hiSLAMF6+ stem-like subset in the spleen with clonotypes shared with homeostatic Th17 cells in the intestinal tissues [26]. The stem-like subset continuously gave rise to a CXCR6+ pathogenic Th17 population also seen in the draining LN and CNS [26], pointing to a migratory role of Th17 cells originating from the gut. In both settings, upregulation of PD-1 and several other co-inhibitory receptors (TIGIT, TIM-3 or LAG3) occurred during the “progenitor” to “mediator” transition [25] or were highly expressed on pathogenic autoreactive T cells in the CNS [26]. Further work is needed to determine the roles of interactions between checkpoint receptors and their ligands in the generation and/or maintenance of autoreactive stem-like cells, as well as their differentiation into pathogenic effector cells.

Parallels to immune-related adverse events with immune checkpoint blockade

A subset of cancer patients treated with antibodies blocking PD-1/PD-L1 or CTLA-4 pathways will develop irAEs. Clinically, irAEs may manifest as inflammation in any organ, most commonly dermatologic, gastrointestinal, pulmonary, and endocrine. The pattern of organ involvement may overlap but is generally distinct between anti-CTLA-4 and anti-PD-1/PD-L1. Notably, combination therapy increases the incidence and severity of irAEs. These toxicities range from mild to life-threatening, requiring immunosuppression and/or treatment discontinuation, either of which may adversely impact therapeutic outcome [27–29]. Multiple mechanisms have been proposed, including a pre-existing susceptibility to autoimmunity, generation of a new self-reactive repertoire, or aberrant presentation of self-antigen in the tumor microenvironment.

Two recent publications profiling checkpoint-inhibitor induced colitis [30] and inflammatory arthritis [31] shed light on differing trafficking patterns of inflammatory irAE-associated T cells. Both studies showed significant tissue infiltration of highly proliferative Th1-like CD4+ T cells and cytotoxic CD8+ T cells expressing high levels of checkpoint receptor genes (Pdcd1, Lag3, Havcr2, and Ctla4). Intriguingly, TCR repertoire analysis showed shared clonal origin among CD8+ effector T cells at the site of the colitis with gut tissue resident memory (TRM cells, suggesting clonal expansion arising from a TRM population [30]. These findings were corroborated by flow cytometry, bulk RNA-sequencing, and single-cell RNA sequencing in a separate cohort of patients with anti-CTLA-4/anti-PD-1 associated colitis and gastritis, which similarly demonstrated enrichment of an activated CD8+ TRM population expressing high levels of PD-1, LAG3 and CTLA-4 with high production of IFNγ, a signature distinct from ulcerative colitis [32].

Studies examining checkpoint-induced inflammatory arthritis showed shared clonality between a CD8+CX3CR1hi effector phenotype in the peripheral blood and CXCR3+CXCRL6+high/low effector memory or terminally differentiated effector memory CD8+ in the synovial fluid [31]. These findings imply active trafficking and differentiation from the peripheral blood to the synovial fluid. Recent work in preclinical mouse arthritis models demonstrated a role for both expansion of TRM in a previously inflamed joint and influx of cells from the periphery [33]. Similarly, single cell analyses from patients with rheumatoid arthritis demonstrated a shared presence of granzyme K-expressing CD8+ T cells between the peripheral blood, inflamed synovial tissue, and synovial fluid [34]. Collectively, these studies suggest that in tissues that lack a TRM population, such as the synovium, trafficking of T cells from the peripheral blood to the inflamed tissue plays a significant role.

Corticosteroids are the mainstay and first-line treatment for severe irAE with organ-specific immunosuppressive strategies employed to treat steroid-refractory irAE. It remains to be understood how the genesis of the immune infiltrate differs to drive steroid-refractoriness. Notably, the study of immune checkpoint-related arthritis identified an increase in Th17 cells in the synovial fluid of subjects treated with combination anti-CTLA-4/anti-PD-1 therapy compared to those subjects treated with anti-PD-1 alone, and the presence of Th17 cells made the inflammatory arthritis less likely to be steroid responsive [31]. How combination therapy would preferentially drive the presence of Th17 cells is unclear.

Immune Checkpoint Ligand Reverse Signaling

Recent work indicates there may be bidirectional functional interactions between immune checkpoint receptors and their ligands. While signaling through the immune checkpoint receptors into T cells is well established, emerging data show that reverse signaling through the ligands of immune checkpoint receptors, such as PD-L1, can exert cell-intrinsic effects. Much of the biology related to this reverse signaling comes from studies of ligand signaling within tumor cells [35]. Deletion of the PD-L1 cytoplasmic tail in tumor cells increased susceptibility to T-cell mediated lysis, indicating PD-L1 plays a critical cell intrinsic role in shielding tumor cells against killing [36]. PD-L1 signaling in tumor cells modulates cell proliferation and motility, mammalian target of rapamycin complex 1 (mTORC1) activation, autophagy, survival, and interferon cytotoxicity [37–40]. Signaling proteins bind the cytoplasmic tail of PD-L1 to transmit biochemical signals [41]. In a tumor model, oncogenic signaling through EGFR recruited phospholipase C-γ1 (PLC-γ1) to the cytoplasmic tail of PD-L1, led to increased protein kinase C activation, Rho GTPases, and calcium flux; and resulted in increased cell motility and invasiveness [42]. Further studies are needed to determine whether similar signaling pathways are activated in non-hematopoietic cells during autoimmunity. For example, PD-L1 upregulation on beta islet cells in the T1D mouse model is driven by IFN expression and has a protective effect on cell survival [43]. This effect could be due, at least in part, to PD-L1 signaling in beta cells.

The PD1-PD-L1 axis also drives cell-intrinsic effects within myeloid cells [44]. Deletion of PD-L1 on DC results in exacerbated EAE through impaired initial activation of CD4+ T cells [45]. PD-L1 is required for proper chemokine mediated dermal dendritic cell migration to the draining lymph node, which is dependent on a three amino acid sequence within the cytoplasmic tail of PD-L1 [46]. Mice containing a deletion in this motif exhibit impaired CCR7 signaling, ultimately hampering CCL21 G protein activation, actin polymerization, and ERK phosphorylation. Defects in dendritic cell migration resulted in reduced T cell priming in infection models requiring dendritic cell trafficking to the lymph node [46]. Collectively, these studies underscore the diverse functions of PD-1/PD-L1 bidirectional signaling events on immune cells and cancer.

Conclusions and future directions

Immune checkpoint receptors such as PD-1, CTLA-4 and LAG3 collectively serve as a rheostat to balance protective immunity, tolerance, immune-mediated tissue damage and homeostasis. They can regulate T cell activation, and fine-tune T cell fates and functions with roles dependent on anatomic location (lymphoid and peripheral tissues), specific immune checkpoint receptor, and T cell type. The presence of genetic polymorphisms in immune checkpoint molecules in humans may layer additional complexity to this rheostat. Given these genetic polymorphisms, targeting immune checkpoint receptors, either by agonistic or antagonistic antibodies, may affect tolerance differently across individuals and provide one explanation for the differing presentations and likelihood of developing immune related adverse events. Further understanding of the multifaceted functions of immune checkpoint receptors and the impact of these genetic polymorphism may provide insights into how to best modulate these pathways to suppress pathologic responses during autoimmunity and promote anti-tumor immunity while limiting irAEs.

Acknowledgments:

We greatly acknowledge thoughtful conversation with K.E. Pauken. Because of space restrictions, we were able to cite only a fraction of the relevant literature and apologize to colleagues whose contributions may not be acknowledged.

Funding:

This work was supported by NIH 5P50CA127003 and P01 CA236749 (to A.H.S.).

K.P.B. was supported by funding from the 2021 AACR-Bristol Myers Squibb Immuno-oncology Research Fellowship, Grant 21–40-15-BURK.

Conflict of Interest Statement:

Arlene Sharpe currently has funding from Quark, Merck, AbbVie, Moderna and Vertex unrelated to the submitted work. She serves on advisory boards for Surface Oncology, SQZ Biotechnologies, Selecta, Elpiscience, Monopteros, Bicara, Fibrogen, and Alixis. She also is on scientific advisory boards for the Massachusetts General Cancer Center, Program in Cellular and Molecular Medicine at Boston Children’s Hospital, the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center, Glaxo Smith Kline and Janssen. She is an academic editor for the Journal of Experimental Medicine. A.H.S. has patents/pending royalties on the PD-1 pathway from Roche and Novartis.

Footnotes

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