The Role of Immune Regulatory Molecules in COVID-19

Abstract

As the fifth pandemic in the 21st century, coronavirus 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the most prominent global concern in the last 2 years. Variable manifestations characterize SARS-CoV-2 infection. Despite the design and production of effective vaccines and their considerable effect on reducing the COVID-19 prevalence and mortality rate, no definitive cure for the disease has yet been found. Mutations may also affect the effectiveness of vaccines. The host immune response to the pathogen has a critical role in the course of the disease. Positive and negative signals often balance the immune system. Immune regulatory molecules, also known as immune checkpoint receptors, balance the immune responses. These molecules mainly have inhibitory functions and prevent hyperactivation of immune cells or trigger adverse signaling pathways. For a decade, the immune checkpoint blockade, as a therapeutic target for cancer immunotherapy, has been utilized. Some of the inhibitory receptors are recognized as exhaustion markers on T cells. The signaling pathway of these markers restricts the function of T cells against viral infection. Dysregulation of T cells was observed in SARS-CoV-2 infection and can modify proliferation, differentiation, cytokine production, and type of response. The pivotal role of immune inhibitory receptors in the function of acquired, cell-mediated, immune defense T cells makes them a fascinating subject to study. This review article summarized recent findings on immune regulatory molecules and their role in SARS-CoV-2 infection, hoping to find a way to design novel treatments.

Introduction

Coronavirus 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in Wuhan, China, in December 2019 and soon became the fifth pandemic of the 21st century (34). SARS-CoV-2 is a single-stranded, positive-sense RNA virus that belongs to the Coronaviridae family. Clinical findings display various signs and symptoms in COVID-19 patients, from asymptomatic to acute respiratory distress syndrome (36).

Based on the evidence, the host immune system acts as a double-edged sword in COVID-19. On one hand, protective immune responses may alleviate the clinical severity of the disease, but on the other hand, immune dysregulation is likely to contribute to disease pathogenesis and mortality (7,21). Positive and negative signals often balance the immune system. This control is steadily kept in check by signaling of inhibitory and stimulatory receptors (13).

For a decade, immune inhibitory receptors, also known as immune checkpoint receptors, have been widely used for cancer immunotherapy to target T cell modulation (24). Immune inhibitory molecules are expressed on various cells in the innate and adaptive immune system and can modulate immune responses. It was suggested that inhibitory receptors are functionally categorized into receptors that control the signaling threshold for immune cell activation and receptors that are engaged in the adverse reactions of immune cell responses (26).

The molecules studied in this article are recognized as exhaustion markers. T cell exhaustion refers to a condition in which T cells maintain expression of inhibitory receptors and therefore restrict their effector function. This state occurs mainly in chronic infections or cancers (37). Evaluation of phenotypic and functional characteristics of T cells revealed that in patients with severe COVID-19, intense dysregulation and apoptosis of T cells occurred (1).

Despite widespread vaccination in many countries of the world and a remarkable reduction in the number of patients with COVID-19 and mortality rate, research about SARS-CoV-2 infection is still undergoing. Unwanted and unpredictable mutations in viral structure may affect the efficacy of vaccines over time and perhaps reduce their function. Besides, no drug has been found for the definitive treatment of this disease.

Accordingly, understanding the molecular mechanisms involved in host immune responses against this virus can help us design effective drugs and vaccines. In this respect, inhibitory receptors are an interesting subject to study. In this review article, we investigated recent observations regarding the role of immune inhibitory molecules in the progression of COVID-19.

T Cell Immunoglobulin and Mucin Domain 3

T cell immunoglobulin and mucin domain 3 (TIM-3), also known as HAVCR2 (hepatitis A virus cellular receptor 2), is a member of the TIM gene family (9). This inhibitory receptor is expressed on various immune system cells, such as Th17, Th1, and Treg cells; CD8⁺ T cells; natural killer (NK) cells; dendritic cells (DCs); and monocytes. Its ligand is mainly galectin-9. TIM-3 signaling by binding to galectin-9 leads to apoptosis, suppressing Th17 and Th1 and modulating immune responses. Nevertheless, recent studies have implied the dual function of TIM-3, so nowadays it is speculated to have both inhibitory and stimulatory activities (4).

In the comparison of malaria and COVID-19, experiments suggested that the level of TIM-3 in T cells was significantly increased in both COVID-19 and malaria patients. In addition, the expression of TIM-3 was higher in patients with severe COVID-19 than in mild patients. However, during recovery, the level of this inhibitory molecule quickly returned to normal. Evaluation of the frequency of activation markers on the surface of CD8⁺ and CD4⁺ T cells illustrated enhanced activation in these cells in acute COVID-19 and malaria patients compared with the healthy control group.

The expression of transcription factors, T-bet and Eomes, was upregulated in the T cells of COVID-19 and malaria patients. It seems that these observations were correlated with increased expression of programmed cell death 1 (PD-1) and TIM-3 (10). It was observed that SARS-CoV-2 affected the number and function of T cells. Analyses showed that CD4⁺ and CD8⁺ T cells decreased substantially in patients with COVID-19. In addition, increased exhaustion markers, TIM-3 and PD-1, reduced the function of T cells (6).

A study on NK cells identified that in patients with COVID-19, the proportion of NK cells in peripheral blood lymphocytes increased, but the proportion of T cells decreased. In NK cells, overexpression of PD-1, TIM-3, and CD69 leads to NK cell exhaustion. However, the expression of these molecules returned to normal after recovery. It seems that a hyperactivated/exhausted phenotype dominated in COVID-19 infection (35).

Analysis of the correlation between immune checkpoint receptors and the severity of disease indicated that the levels of soluble T-cell immunoglobulin mucin domain-3, galectin-9, soluble programmed death-ligand-1, and soluble programmed death-1 increased in severe patients compared with mild patients. On the other hand, ex vivo use of anti-TIM-3 and anti-galectin-9 blocking antibodies showed a considerable increase in the response and a decrement in apoptosis of CD4⁺ and CD8⁺ T cells in COVID-19 patients.

This study claims that immune checkpoint inhibitors on admission can better predict mortality than other biomarkers such as cytokines in COVID-19 (3). However, a meta-analysis study suggested that patients who received immune checkpoint inhibitor regimens have a higher risk for hospitalization (22).

Thymosin α 1 (Tα1) is a polypeptide hormone that is used to treat viral infections. It fights viral infections by enhancing the number and differentiation of T cells. Treatment of severe COVID-19 patients with Tα1 reduced the expression of TIM-3 and PD-1 on the surface of CD8⁺ T cells. Tα1 boosted thymus output and increased TCR diversity, hence T cell exhaustion was reversed. The mortality rate in these patients was significantly reduced compared with the control group (12).

Based on the evidence, the expression of TIM-3 in COVID-19 patients was increased, which seems to be transient and is correlated with the severity of the disease. Due to the role of the TIM-3 molecule in reducing the function of T and NK cells, it may be possible to restore the strength of the immune system in response to SARS-CoV-2 by inhibiting TIM-3 signaling.

The B and T Lymphocyte Attenuator

The B and T lymphocyte attenuator (BTLA or CD272) belongs to the immunoglobulin superfamily. It can be expressed on NK cells, macrophages, DCs, NKT cells, T and B cells, and T follicular helper (TFH) cells. B7H4 and herpesvirus entry mediator as the ligand can bind to BTLA and result in prevention of interleukin-2 (IL-2) production and T cell activation, which conversely enhances anti-inflammatory cytokine production, such as IL-10 (18).

Assessment of the frequency of immune checkpoints showed that the expression of BTLA mRNA during SARS-CoV-2 infection was increased (27). The level of BTLA in memory CD4⁺ and CD8⁺ T cells was lower than in naive subsets of these cells in malaria patients, COVID-19 patients, and healthy controls, whereas the respective decrease in healthy individuals was greater than in malaria and COVID-19 patients.

Elevated expression of BTLA on transitional memory and effector memory CD8⁺ T cells was detected in COVID-19 and malaria patients compared with healthy subjects (10). More investigation is needed in the role of BTLA in COVID-19 disease. In addition, the difference in BTLA expression in various cells and different stages of differentiation makes it a proper target for future studies.

Programmed Cell Death 1

PD-1, or CD279, is an essential member of the CD28/cytotoxic T lymphocyte antigen 4 (CTLA-4) family that is expressed on T cells, Tregs, T follicular regulatory cells, TFH cells, tolerant T cells, and memory T cells, as well as B cells, NK cells, cancer cells, and also some myeloid cells. PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273) are ligands for PD-1, and their interaction initiates inhibitory mechanisms of T cell activation and immune tolerance (31).

Sattler et al. demonstrated that the expression of PD-1 on CD4⁺ T cells, which increased in the acute phase, decreased during recovery (29). It was suggested that the expression of PD-1 on CD4⁺ and CD8⁺ T cells was related to an improved immune response to antigens presented by autologous DCs (32). The highest level of expression of PD-1 on CD4⁺ T cells was simultaneously detected in patients with hematologic malignancies and COVID-19.

Additionally, the most marked impairment of SARS-CoV-2 cross-reactive CD4⁺ T cells was observed. Indeed, increased expression of PD-1 causes dysfunction of T cells and limits their function to respond to viral infections (28). It was observed that in patients with lung cancer, blockade of PD-1 did not affect the increased risk of severity of COVID-19 (15). A case report showed that treatment with anti-PD-1 in a metastatic melanoma patient, also diagnosed with COVID-19, had no side effects (19).

In a study conducted to investigate the function of T cells in peripheral blood mononuclear cells of COVID-19 patients, memory CD8⁺ T cells that were stimulated with peptide showed a capacity to proliferate regardless of disease severity. The proportion of CD8⁺ T cells that produced interferon-γ (IFN-γ) was substantially higher in PD-1⁺ cells than in PD-1⁻ cells regardless of disease severity. In this respect, these experimental data showed that T cells are functional, although they express the inhibitory marker PD-1 (23).

In patients with severe SARS-CoV-2 infection, the count of CD8⁺ T cells that displayed an exhausted phenotype was significantly higher than in patients with mild symptoms. Blockade of PD-1 and CTLA-4 reversed exhaustion of CD8⁺ T cells; therefore, immunity against SARS-CoV-2 was boosted and antiviral function improved (38). In patients with COVID-19 who have shown a higher level of IL-10, PD-1/PD-L1 interaction can lead to deterioration in the viral infection and monocyte reconfiguration (20).

In patients who recovered from COVID-19, T cells reflected an exhausted phenotype and PD-1⁺ T cells were increased compared with healthy subjects. In this regard, the response of T cells to SARS-CoV-2 antigens was impaired and ex vivo blockade of PD-1 reverted T cell function (14). In addition, in IFN-γ ⁺ CD4⁺ T cells of convalescent patients at 1 year postinfection, exhaustion marker levels (TIM-3, PD-1, and CTLA-4) were higher than in IFN-γ ⁻ CD4⁺ T cells (11).

The exhausted phenotype of T lymphocytes in older patients was detected. The level of expression of TIM-3 and PD-1 on both CD4⁺ and CD8⁺ T cells increased substantially in older patients. It can lead to repression of immune responses against the SARS-CoV-2 (2). In this regard, studies have shown that older patients with COVID-19 have a higher risk of severe disease and mortality (17).

In parallel with similar studies on other immune checkpoint inhibitors, most findings showed that the expression of PD-1 increased transiently and had a negative effect on T cell function. However, Rha et al. contradictorily demonstrated that T cells are functional despite PD-1 overexpression. It seems that further studies are needed in this regard. On the other hand, the history of immunotherapy in cancers with PD-1 blockade and the lack of side effects in patients with COVID-19 show promising potential for COVID-19 immunotherapy.

Cytotoxic T Lymphocyte Antigen 4

CTLA-4, also known as CD152, is an immunoglobulin superfamily member. It has mostly been found on activated T cells and Treg cells. B7-2 (CD86) and B7-1 (CD80) are both ligands for CTLA-4. CTLA-4 is a regulatory receptor that restricts the function of T cells, such as proliferation and IL-2 production (25).

In the comparison between ICU patients and convalescent patients, it was illustrated that expression of CTLA-4 was markedly upregulated in specific T cells in ICU patients. The levels of CTLA-4 and PD-1 in CD4⁺ and CD8⁺ T cells of ICU patients were significantly higher than healthy controls, but the relevant expression in convalescent subjects was lower and similar to controls.

In parallel with overexpression of CTLA-4, the diversity of function of SARS-CoV-2-specific T cells in severe patients was restricted and the cytokine expression profile was also limited. The rate of expression seems to be related to the severity of disease. In convalescent subjects, downregulation of CTLA-4 leads to better viral control, while the higher level of CTLA-4 on SARS-CoV-2-specific T cells in patients with severe disease is concomitant with the long-term and stronger encounter with the virus (30). It was identified that in the CD8⁺ T cell population, the number of nonexhausted (PD-1⁻CTLA-4⁻TIGIT⁻) subsets in the acute group was notably diminished compared with mild patients and healthy controls (38).

Neidleman et al. considered T cells with elevated expression of PD-1 and TIGIT or PD-1 and CTLA-4 exhausted cells. According to this, a dramatic elevation in exhausted T cells was observed in severe COVID-19 patients. Based on previous studies and the above data, a correlation between T cell exhaustion and disease severity was established. They also reported that PD-1⁺ CD95⁺ T cells were increased in severe patients compared with the mild group.

The previous study revealed an increase in apoptotic T cells during the severe course. Therefore, Neidleman et al. suggested that T cells were exhausted and apoptosis-prone during severe COVID-19. This may result in a reduction in the number of T cells and their function, which may impair the immune response (16).

These findings suggest that CTLA-4 may have a role in T cell dysfunction. Further studies can focus on the use of anti-CTLA-4 in COVID-19 patients and its effect on the severity of the disease.

Glucocorticoid-Induced Tumor Necrosis Factor Receptor-Related Protein

The glucocorticoid-induced Tumor Necrosis Factor Receptor (TNFR)-related protein (GITR) belongs to the TNFR superfamily. GITR is expressed on T cells, some myeloid cells, and also NK cells. Interaction between GITR and its ligand, GITRL, can regulate both innate and adaptive immune responses (33).

De Biasi et al. indicated that by measuring plasma levels of immune receptors in 21 patients and 13 healthy controls, it was revealed that GITR was overtly elevated in COVID-19 patients (5). TTD (TTDPSFLGRY) is a unique epitope of SARS-CoV-2. It was indicated that expression of the GITR gene in TTD-specific CD8⁺ T cells was downregulated (8). Although results of these two studies on expression of GITR are contradictory, it seems that studies on this inhibitory receptor have been limited, and more information is needed about the function of this molecule in COVID-19 disease.

Table 1 shows the expression of inhibitory receptors in COVID-19.

Table 1.

The Expression of Inhibitory Receptors in COVID-19

Molecule	Cells or sample	Expression	Reference
TIM-3	T cells of COVID-19 patients	Upregulated compared with T cells of healthy controls	Herrmann et al. (10)
	Patients with severe COVID-19	Higher than patients with mild COVID-19	Herrmann et al. (10)
	NK cells of COVID-19 patients	Upregulated compared with NK cells of healthy controls	Varchetta et al. (35)
	CD8⁺ T cells of severe COVID-19 patients	Downregulated after treatment with Tα1	Liu et al. (12)
	Severe patients	Increased compared with mild patients	Avendaño-Ortiz et al. (3)
	IFN-γ ⁺ CD4⁺ T cells of convalescent patients at 1 year postinfection	Higher than IFN-γ ⁻ CD4⁺ T cells	Hou et al. (11)
	CD4⁺ and CD8⁺ T cells in older patients (>60 years)	Higher than younger patients (<60 years)	Angioni et al. (2)
BTLA	PBMCs of COVID-19 patients	Upregulated compared with PBMCs of healthy controls	Saheb Sharif-Askari et al. (27)
	Memory CD4⁺ and CD8⁺ T cells of COVID-19 patients	Lower than naive CD4⁺ and CD8⁺ T cells of COVID-19 patients	Herrmann et al. (10)
	Transitional memory and effector memory CD8⁺ T cells of COVID-19 patients	Upregulated compared with healthy controls	Herrmann et al. (10)
PD-1	CD8⁺ T cells of severe COVID-19 patients	Downregulated after treatment with Tα1	Liu et al. (12)
	NK cells of COVID-19 patients	Upregulated compared with healthy controls	Varchetta et al. (35)
	CD4⁺ T cells in recovery	Downregulated compared with CD4⁺ T cells in the acute phase	Sattler et al. (29)
	PD-1⁺ T cells in recovered patients	Increased compared with healthy controls	Loretelli et al. (14)
	The count of CD8⁺ T cells with exhausted phenotype in severe COVID-19	Higher than mild COVID-19	Zheng et al. (38)
	CD4⁺ and CD8⁺ T cells of ICU patients	Higher than healthy controls	Schub et al. (30)
	CD4⁺ and CD8⁺ T cells of convalescent patients	Similar to healthy controls	Schub et al. (30)
	IFN-γ ⁺ CD4⁺ T cells of convalescent patients at 1 year postinfection	Higher than IFN-γ ⁻ CD4⁺ T cells	Hou et al. (11)
	Severe patients	Increased compared with mild patients	Avendaño-Ortiz et al. (3)
	CD4⁺ and CD8⁺ T cells in older patients (>60 years)	Higher than younger patients (<60 years)	Angioni et al. (2)
CTLA-4	Specific T cells in ICU patients	Upregulated compared with convalescent patients	Schub et al. (30)
	CD4⁺ and CD8⁺ T cells of ICU patients	Higher than healthy controls	Schub et al. (30)
	CD4⁺ and CD8⁺ T cells of convalescent patients	Similar to healthy controls	Schub et al. (30)
	The number of nonexhausted (PD-1⁻CTLA-4⁻TIGIT⁻) CD8⁺ T cells in the acute group	Lower than mild patients and healthy controls	Zheng et al. (38)
	IFN-γ ⁺ CD4⁺ T cells of convalescent patients at 1 year postinfection	Higher than IFN-γ⁻ CD4⁺ T cells	Hou et al. (11)
GITR	Plasma level	Higher than healthy controls	De Biasi et al. (5)
GITR	TTD-specific CD8⁺ T cells	Downregulated compared with CD8⁺ T cells	Gangaev et al. (8)

BTLA, B and T lymphocyte attenuator; COVID-19, coronavirus 2019; CTLA-4, cytotoxic T lymphocyte antigen 4; IFN-γ, interferon-γ; NK, natural killer; PBMCs, peripheral blood mononuclear cells; PD-1, programmed cell death 1; Tα1, thymosin α 1; TIM-3, T cell immunoglobulin and mucin domain 3.

Conclusions

COVID-19 disease, as the greatest global concern of the last 2 years, has led to severe and sometimes irreparable damage to human health. In this review article, we focused on inhibitory molecules and their effects on SARS-CoV-2 infection. Inhibitory receptors are mainly expressed on T cells. Previous research revealed their potential contribution to T cell dysregulation. The augmented expression of these molecules in COVID-19 patients, along with its relationship with deterioration of the disease, indicates their effect on immune responses and their ineffectiveness.

Although this increase is transient and in the convalescent phase, it could be returned to the normal level. The expression of inhibitory receptors causes an exhaustion phenotype in immune cells and restricts the function of these cells. The treatment of cancer patients, also diagnosed with COVID-19, with immune checkpoint blockade drugs indicates improvement of the disease without side effects. Previous experiences in treating cancer patients with immune checkpoint blockade drugs may help to understand the involved molecular mechanisms.

It seems that more studies are needed in this field; accurate knowledge of pathogenic mechanisms and the role of immune inhibitory molecules in SARS-CoV-2 infection can help us to overcome this infection. Based on these findings, it is possible to seek new treatment strategies by targeting immune checkpoint receptors and blocking their signaling pathways. Subsequent studies could identify the signaling pathways of these receptors and their effects on cell function and consequent disease manifestations.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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