What Are the Immunomodulatory Roles of Red Blood Cells?
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Immunomodulatory Roles of Red Blood Cells - Functions and Recent Advancements

Published on Apr 20, 2023   -  5 min read


Red blood cells (RBCs) play an important role in regulating the immune system through various immunomodulatory mechanisms. Read on to learn more.


Red blood cells (RBCs) are typically recognized for their function in the transportation of oxygen, but new research has revealed that they also have a significant impact on immune system control. Several immunomodulatory roles for RBCs have been discovered, including cytokine level regulation, complement activation modulation, antigen presentation, T cell activation modulation, and dendritic cell function regulation. Recognizing the immunomodulatory functions of RBCs can shed light on the pathophysiology of several illnesses and pave the way for the creation of novel treatment approaches. The many ways that RBCs might control the immune response will be covered in-depth in this article.

What Are Red Blood Cells?

The most prevalent form of blood cell in the human body are red blood cells, or erythrocytes. They have a biconcave shape and no nucleus, which gives them greater room to transport oxygen and carbon dioxide. RBCs are largely in charge of bringing carbon dioxide back to the lungs for exhalation and transferring oxygen from the lungs to the body's tissues and organs. RBCs have a distinctive red hue because of hemoglobin, a protein that binds to oxygen and carbon dioxide. RBCs are created in the bone marrow and circulate for around 120 days before being eliminated through the spleen and liver.

What Are the Different Immunomodulatory Roles of Cytokines?

RBCs have a number of ways to control cytokine levels, including:

  • Cytokine Scavenging: Pro-inflammatory cytokines including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) have been found to be scavenged from the circulation by RBCs. Its scavenging function can lessen tissue damage and excessive cytokine production during inflammation.

  • Cytokine Production: RBCs can manufacture cytokines including erythropoietin (EPO) and transforming growth factor-beta (TGF-) on their own. Although TGF- has been proven to have immunosuppressive effects, EPO has been demonstrated to increase the synthesis of red blood cells and to have anti-inflammatory effects.

  • Adenosine Triphosphate (ATP) Release: RBCs respond to hypoxia by releasing adenosine triphosphate (ATP).

  • Heme Oxygenase-1 (HO-1) Production: RBCs generate heme oxygenase-1 (HO-1) in response to oxidative stress. HO-1 has anti-inflammatory properties and can decrease cytokine production.

Many illnesses, including sepsis and autoimmune disorders, have been linked to dysregulation of the cytokine system. Knowing the immunomodulatory functions of RBCs may offer fresh perspectives on the causes of various disorders and pave the way for the creation of novel treatment approaches.

  • Modulation of complementary systems.

  • The term "complementary system" refers to a group of blood proteins that cooperate to recognize and eliminate foreign substances like bacteria and viruses. Red blood cells (RBCs) lack this system but have a variety of ways to control the activity.

  • The expression of complement regulatory proteins on their surface is one method. These proteins (such as CD55 and CD59) prevent the activation of the complement system on the RBC surface, thereby protecting the cell from complement-mediated damage.

  • RBCs can also manufacture complement components themselves, notably complement component C3. This may play a role in the clearance of immune complexes and other debris from the blood.

  • Moreover, RBCs can interact with complement proteins in a number of ways. For example, RBCs can bind to complement proteins such as C1q and C3b, which can facilitate the clearance of immune complexes and other particles from the circulation.

Overall, while RBCs do not have a complementary system of their own, they can interact with and modulate the activity of this important component of the immune system in several ways.

  • Due to the lack of the machinery necessary for antigen presentation, such as the major histocompatibility complex (MHC) molecules, red blood cells (RBCs) typically do not present antigens to T cells. However, there are some circumstances in which RBCs can contribute to immunomodulation through antigen presentation.

  • One example is in the context of autoimmune hemolytic anemia (AIHA), a condition in which the immune system mistakenly attacks and destroys RBCs. In this case, the RBCs may be coated with autoantibodies, which can then be recognised by antigen-presenting cells (APCs) such as dendritic cells. These APCs can then present the RBC-derived autoantigens to T cells, leading to the activation of an autoimmune response.

  • Another example is in the context of transfusion reactions, where RBCs from a donor with a different blood type are transfused into a recipient. In this case, the recipient's immune system may recognise the donor RBCs as foreign and mount an immune response. This immune response may involve the presentation of antigens derived from donor RBCs by APCs, which causes T cells to become activated and produce antibodies against the donor RBCs.

In both of these scenarios, RBCs can indirectly contribute to antigen presentation and subsequent immunomodulation, although this is not a typical function of RBCs under normal circumstances.

Here are some possible ways that RBCs could modulate T cell activation:

  • Cytokine Secretion: RBCs can secrete cytokines such as TGF-β, which can inhibit T cell activation and proliferation. TGF-β can also promote the development of regulatory T cells (Tregs), which can further suppress T cell activation.

  • Antigen Presentation: While RBCs do not typically present antigens to T cells, they can present antigens in certain contexts such as autoimmune hemolytic anemia. In these cases, RBC-derived autoantigens could be presented to T cells by antigen-presenting cells, leading to T cell activation and potentially contributing to autoimmune responses.

  • Modulation of Dendritic Cells: RBCs can interact with dendritic cells, which are professional antigen-presenting cells that play a critical role in T cell activation. RBCs have been shown to modulate dendritic cell function and maturation, which can affect T cell activation.

  • Direct Interaction With T Cells: RBCs have been shown to interact directly with T cells, although the functional consequences of this interaction are not clear. Some studies have suggested that RBCs can suppress T cell activation, while others have found that RBCs can enhance T cell activation.

  • Regulation of Dendritic Cell Function: Dendritic cells are immune cells that play a crucial role in antigen presentation and the activation of the immune response. RBCs have been shown to regulate dendritic cell function by producing heme oxygenase-1 (HO-1) in response to oxidative stress. HO-1 can inhibit dendritic cell maturation and activation, leading to a decrease in the immune response.

What Are the Recent Findings?

Throughout the past century, research has shown that red blood cells have additional activities, such as immunological activity, in addition to carrying oxygen. According to recent research, the nucleic acid sensing receptor toll-like receptor 9 (TLR9) is expressed on the surface of red blood cells and is involved in the activation of the innate immune system and the removal of red blood cells during inflammatory situations. In addition to their function as DNA sensors, RBCs may also affect immune function by causing vascular dysfunction, according to mounting research.

With multiple studies revealing changes to RBC membrane structure and metabolism in response to severe acute respiratory syndrome and Coronavirus 2 infection, RBC proteomics and metabolomics have added to one’s understanding of how RBC immune function functions.

Lastly, evidence points to the possibility that RBCs regulate complement in a manner that affects host immunological responses. Taken together, these new data imply that RBCs contain immunological activity.


In conclusion, RBCs play a crucial role in modulating the immune response through various mechanisms that can help prevent excessive immune activation and tissue damage during inflammation. Future studies are needed to fully understand the complex interactions between RBCs and the immune system and how these interactions can be harnessed for therapeutic purposes.

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20 Apr 2023  -  5 min read




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